US5498609A - Benzoazepinyl compounds as oxytocin and vasopressin antagonists - Google Patents

Benzoazepinyl compounds as oxytocin and vasopressin antagonists Download PDF

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US5498609A
US5498609A US08/211,887 US21188794A US5498609A US 5498609 A US5498609 A US 5498609A US 21188794 A US21188794 A US 21188794A US 5498609 A US5498609 A US 5498609A
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lower alkyl
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Hidenori Ogawa
Kazumi Kondo
Hiroshi Yamashita
Keizo Kan
Michiaki Tominaga
Yoichi Yabuuchi
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Otsuka Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to novel benzoheterocyclic compounds which are useful as medicines.
  • An object of the present invention is to provide benzoheterocyclic compounds of the formula (1): ##STR2## wherein R 1 is hydrogen atom or a halogen atom,
  • R 2 is hydrogen atom, oxo group, a lower alkylidene group, hydroxy group, a lower alkoxy group, a lower alkenyloxy group, a hydroxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkylsulfonyloxy-substituted lower alkoxy group, a phthalimide-substituted lower alkoxy group, a hydroxy-substituted lower alkyl group, a group of the formula: --O--D--(CO) I NR 4 R 5 (wherein D is a lower alkylene group, I is 0 or 1, R 4 and R 5 are the same or different and are hydrogen atom, a lower alkyl group, a lower alkanoyl group, a cycloalkyl group, or an amino-substituted lower al
  • R 3 is hydrogen atom, a lower alkoxy group or a hydroxy-substituted lower alkyl group
  • B 1 and B2 are each methylene group or a group of the formula: --NR 8 -- (wherein R 8 is hydrogen atom or a lower alkyl group),
  • A is a 5- or 6-membered unsaturated heterocyclic residue having 1 to 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
  • R is a group of the formula: --NHR A or a group of the formula: ##STR3## wherein R A is a group of the formula: ##STR4## [wherein m is an integer of 1 to 3, R 18 is hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, nitro group, a lower alkoxycarbonyl group, carboxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a hydroxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkylsulfonyloxy-substituted lower alkoxy group, a phthalimide-substituted lower alkoxy group, or a group of the formula: --O--E--(CO) I NR 19 R 20 (wherein E and I are the same as defined above, R 19 and R 20 are the same or different and are hydrogen atom or
  • the compounds of the formula (1) of the present invention and salts thereof show excellent vasopressin antagonistic activities, for examples, vasodilating activity, hypotensive activity, activity for inhibiting saccharide release in liver, activity for inhibiting growth of mesangium cells, water diuretic activity, platelet agglutination inhibitory activity, inhibitory activity for vomiting, and hence, they are useful as vasodilators, hypotensive agents, water diuretics, platelet agglutination inhibitor, etc., and are used in the prophylaxis or treatment of hypertension, edema, ascites, heart failure, renal function disorder, vasopressin parasecretion syndrome (SIADH), hepatocirrhosis, hyponatremia, hypokalemia, diabetic, circulation disorder, motion sickness, and the like.
  • vasopressin antagonistic activities for examples, vasodilating activity, hypotensive activity, activity for inhibiting saccharide release in liver, activity for inhibiting growth of mesangium cells
  • the compounds of the present invention and salts thereof show oxytocin antagonistic activities, for example, inhibitory effect on uterine smooth muscle constriction, inhibitory effect on milk secretion, inhibitory effect on synthesis and secretion of prostaglandin, and vasodilation activity, and hence, are useful in the protection or treatment of oxytocin-associated diseases, especially premature delivery, dysmenorrhea, endometritis, or in stopping labor preparatory to Caesarian delivery.
  • the compounds of the present invention and salts thereof are characteristic in less side effects, and in prolonged action for a long time in living body.
  • Each group in the above formula (1) specifically includes the following groups.
  • the "lower alkoxy group” includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, and the like.
  • the "lower alkyl group” includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like.
  • halogen atom includes fluorine atom, chlorine atom, bromine atom, and iodine atom.
  • the "lower alkylene group” includes a straight chain or branched chain alkylene group having 1 to 6 carbon atoms, for example, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene, and the like.
  • the "hydroxy-substituted lower alkoxy group” includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by 1 to 3 hydroxy groups, for example, hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxyethoxy, 4-hydroxybutoxy, 3,4-dihydroxybutoxy, 1,1-dimethyl-2-hydroxyethoxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy, 2-methyl-3-hydroxypropoxy, 2,3,4-trihydroxybutoxy, and the like,
  • the "lower alkanoyl group” includes a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, t-butylcarbonyl, hexanoyl, and the like.
  • the "carboxy-substituted lower alkyl group” includes a carboxyalkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, carboxymethyl, 2-carboxylethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1,1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyl, and the like.
  • the "5- or 6-membered saturated heterocyclic group which is formed by combining the groups R 4 and R 5 , or the groups of R 6 and R 7 with the nitrogen atom to which they bond, which may be intervened or not with nitrogen atom, oxygen atom or sulfur atom” includes pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, and the like.
  • the "above mentioned heterocyclic group which is substituted by a lower alkyl group or a lower alkanoyl group” includes the above mentioned heterocyclic groups which are substituted by 1 to 3 groups selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2 -propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 3-methylthiomorpholino, 4-hexylpiperazinyl, 4-acetylpiperazinyl, 4-formyl-3-methylpiperazinyl, 3-propionylpyrrolidinyl, 2-butyrylpyrrolidinyl, 4-pentanoylpiperidinyl,
  • the "above mentioned heterocyclic groups substituted by a lower alkyl group, a lower alkanoyl group or a lower alkoxycarbonyl group” includes the above mentioned heterocyclic groups substituted by 1 to 3 groups selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms and a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 3-methylthiomorpholino, 4-hexylpiperazinyl, 4-acetylpiperazinyl, 4-formyl-3-methylpiperazinyl
  • the "5- or 6-membered unsaturated heterocyclic residue having 1 to 2 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom” includes imidazolyl, pyrrolyl, imidazolinyl, pyridyl, primidyl, oxazolyl, pyrazolyl, pyrazolinyl, thiazolyl, thiazolinyl, thienyl, furyl, pyranyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrrolinyl, and the like.
  • cycloalkylcarbonyl group includes a cycloalkylcarbonyl group having 3 to 8 carbon atoms in the cycloalkyl moiety, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, and the like.
  • phenyl-lower alkanoyl wherein the phenyl moiety may optionally have a lower alkyl substituent includes phenylalkanoyl groups wherein the phenyl ring may optionally have 1 to 3 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and the alkanoyl moiety is a straight chain or branched chain alkanoyl group having 2 to 6 carbon atoms, for example, phenylacetyl, 3-phenylpropionyl, 2-phenylpropionyl, 4-phenylbutyryl, 2,2-dimethyl-3-phenylpropionyl, 5-phenylpentanoyl, 6-phenylhexanoyl, (2-methylphenyl)acetyl, (3-methylphenyl)acetyl, (4-methylphenyl)acetyl, 2-(2-ethylphenyl)propionyl, 3-(3-isopropy
  • the "hydroxy-substituted lower alkyl group” includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which has 1 to 3 hydroxy substituents, for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyethyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl, 6-hydroxyhexyl, 2-methyl-3-hydroxypropyl, 2,3,4-trihydroxybutyl, and the like.
  • hydroxy substituents for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyethyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl, 6-hydroxyhexyl, 2-methyl-3-hydroxypropyl, 2,3,4
  • the "lower alkylidene group” includes a straight chain or branched chain alkylidene group having 1 to 6 carbon atoms, for example, methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene, hexylidene, and the like.
  • the "lower alkoxycarbonyl-substituted lower alkoxy group” includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, methoxycarbonylmethoxy, 3-methoxycarbonylpropoxy, ethoxycarbonylmethoxy, 3-ethoxycarbonylpropoxy, 4-ethoxycarbonylbutoxy, 5-isopropoxycarbonylpentyloxy, 6-propoxycarbonylhexyloxy, 1,1-dimethyl-2-butoxycarbonylethoxy, 2-methyl-3-t-butoxycarbonylpropoxy, 2-pentyloxycarbonylethoxy, hexyloxycarbonylmethoxy, and the like.
  • the "carboxy-substituted lower alkoxy group” includes a carboxyalkoxy group wherein the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, carboxymethoxy, 2-carboxyethoxy, 1-carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy, 1,1-dimethyl-2-carboxyethoxy, 2-methyl-3-carboxypropoxy, and the like.
  • the "lower alkylsulfonyloxy-substituted lower alkoxy group” includes an alkylsulfonyloxyalkoxy group wherein the alkylsulfonyloxy moiety is a straight chain or branched chain alkylsulfonyloxy group having 1 to 6 carbon atoms and the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methylsulfonyloxymethoxy, 3-methylsulfonyloxypropoxy, ethylsulfonyloxymethoxy, 3-ethylsulfonyloxypropoxy, 2-methylsulfonyloxyethoxy, 4-ethylsulfonyloxybutoxy, 5-isopropylsulfonyloxypentyloxy, 6-propylsulfonyloxyhexyloxy, 1,1-dimethyl-2-butylsulfon
  • the "phthalimide-substituted lower alkoxy”: group includes a phthalimide-substituted alkoxy group wherein the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, phthalimidomethoxy, 2-phthalimidoethoxy, 1-phthalimidoethoxy, 3-phthalimidopropoxy, 4-phthalimidobutoxy, 5-phthalimidopentyloxy, 6-phthalimidohexyloxy, 1,1-dimethyl-2-phthalimidoethoxy, 2-methyl-3-phthalimidopropoxy, and the like.
  • the "lower alkoxycarbonyl-substituted lower alkyl group” includes an alkoxycarbonylalkyl group wherein the alkoxycarbonyl moiety is a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety and the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methoxycarbonylmethyl, 3-methoxycarbonylpropyl, ethoxycarbonylmethyl, 3-ethoxycarobnylpropyl, 4-ethoxycarbonylbutyl, 5-isopropoxycarbonylpentyl, 6-propoxycarbonylhexyl, 1,1-dimethyl-2-butoxycarbonylethyl, 2-methyl-3-t-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl, hexyloxycarbonylmethyl, and the like.
  • amino which may optionally have 1 to 2 substituents of a lower alkyl group or a cycloalkyl group includes an amino which may optionally be substituted by a straight chain or branched chain alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, for example, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino, cyclopropylamino, cyclopropyla
  • the "lower alkenyloxy group” includes a straight chain or branched chain alkenyloxy group having 2 to 6 carbon atoms, for example, vinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 1-methylallyloxy, 2-pentenyloxy, 2-hexenyloxy, and the like.
  • cycloalkyl group includes cycloalkyl groups having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, and the like.
  • amino-substituted lower alkyl group which may optionally have a lower alkyl substituent includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by an amino group optionally having 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylamin
  • the "lower alkoxycarbonyl group” includes a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyoxycarbonyl, and the like.
  • the "lower alkanoyloxy-substituted lower alkyl group” includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkanoyloxy group having 2 to 6 carbon atoms, for example, acetyloxymethyl, 2-acetyloxyethyl, 3-propionyloxypropyl, 4-butyryloxybutyl, 5-isobutyryloxypentyl, 1,1-dimethyl-2-pentanoyloxyethyl, 5-hexanoyloxypentyl, 6-acetyloxyhexyl, 2-methyl-3-acetyloxypropyl, and the like.
  • lower alkylsulfonyloxy-substituted lower alkyl group includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkylsulfonyloxy group having 1 to 6 carbon atoms, for example, methylsulfonyloxymethyl, 3-methylsulfonyloxypropyl, ethylsulfonyloxymethyl, 3-ethylsulfonyloxypropyl, 2-methylsulfonyloxyethyl, 4-ethylsulfonyloxybutyl, 5-isopropylsulfonyloxypentyl, 6-propylsulfonyloxyhexyl, 1,1-dimethyl-2-butylsulfonyloxyethyl, 2-methyl-3-t-butylsulfonyloxypropyl, 2-pentylsulfon
  • the "phthalimide-substituted lower alkyl group” includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a phthalimide group, for example, phthalimidomethyl, 2-phthalimidoethyl, 1-phthalimidoethyl, 3-phthalimidopropyl, 4-phthalimidobutyl, 5-phthalimidopentyl, 6-phthalimidohexyl, 1,1-dimethyl-2-phthalimidoethyl, 2-methyl-3-phthalimidopropyl, and the like.
  • a phthalimide group for example, phthalimidomethyl, 2-phthalimidoethyl, 1-phthalimidoethyl, 3-phthalimidopropyl, 4-phthalimidobutyl, 5-phthalimidopentyl, 6-phthalimidohexyl, 1,1-dimethyl-2-phthalimidoethyl, 2-methyl-3-phthalimidoprop
  • the "imidazolyl-substituted lower alkyl group” includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by an imidazolyl group, for example, (1-imidazolyl)methyl, 2-(1-imidazolyl)ethyl, 1-(2-imidazolyl)ethyl, 3-(4-imidazolyl)propyl, 4-(5-imidazolyl)butyl, 5-(1 -imidazolyl)pentyl, 6-(2-imidazolyl)hexyl, 1,1-dimethyl-2-(1-imidazolyl)ethyl, 2-methyl-3-(1-imidazolyl)propyl, and the like.
  • imidazolyl group for example, (1-imidazolyl)methyl, 2-(1-imidazolyl)ethyl, 1-(2-imidazolyl)ethyl, 3-(4-imidazo
  • the "1,2,4-triazolyl-substituted lower alkyl group” includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a 1,2,4-triazolyl group, for example, (1,2,4-triazol-1-yl)methyl, 2-(1,2,4-triazol-1-yl)ethyl, 1-(1,2,4-triazol-1-yl)ethyl, 3-(1,2,4-triazol-3-yl)propyl, 4-(1,2,4-triazol-5-yl)butyl, 5-(1,2,4-triazol- 1 -yl)pentyl, 6-(1,2,4-triazol-3-yl)hexyl, 1,1-dimethyl-2-(1,2,4-triazol-5-yl)ethyl, 2-methyl-3-(1,2,4-triazol-1-yl)propyl, and the like.
  • the "imidazolyl-substituted lower alkoxy group” includes a straight chain or branched chain alkoxyl group having 1 to 6 carbon atoms which is substituted by an imidazolyl group, for example, (1-imidazolyl)methoxy, 2-(1-imidazolyl)ethoxy, 1-(2-imidazolyl)ethoxy, 3-(4-imidazolyl)propoxy, 4-(5-imidazolyl)butoxy, 5-(1 -imidazolyl)pentyloxy, 6-(2-imidazolyl)hexyloxy, 1,1-dimethyl-2-(1-imidazolyl)ethoxy, 2-methyl-3-(1-imidazolyl)propoxy, and the like.
  • amino-substituted lower alkanoyloxy group which may optionally have a lower alkyl substituent includes a straight chain or branched chain alkanoyloxy group having 2 to 6 carbon atoms which is substituted by an amino group optionally being substituted by 1 to 2 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms, for example, 2-aminoacetyloxy, 3-aminopropionyloxy, 2-aminopropionyloxy, 4-aminobutyryloxy, 5-aminopentanoyloxy, 6-aminohexanoyloxy, 2,2-dimethyl-3-aminopropionyloxy, 2-methyl-3-aminopropionyloxy, 2-methylaminoacetyloxy, 2-ethylaminopropionyloxy, 3-propylaminopropionyloxy, 3-isopropylaminopropionyloxy, 4-butylaminobutyryloxy, 5-pentyla
  • an amino group which may optionally have a lower alkanoyl substituent includes an amino group which may optionally have a substituent of a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, amino, acetylamino, propionylamino, isopropionylamino, butyrylamino, pentanoylamino, hexanoylamino, formylamino, and the like.
  • the "5- or 6-membered saturated heterocyclic group which is formed by combining the groups R 19 and R 20 with the nitrogen atom to which they bond, which may be intervened or not with nitrogen atom or oxygen atom” includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, and the like.
  • the "above mentioned heterocyclic groups which are substituted by an amino group optionally being substituted by a lower alkyl group or a lower alkanoyl group” includes, for example, the above mentioned heterocyclic groups which are substituted by 1 to 3 amino groups optionally being substituted by a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, or a straight chain or branched chain alkanoyl group having 1 to carbon atoms, for example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 3-methyl-4-acetylaminopiperidinyl, 4-hexylpiperazinyl, 4-acetylaminopiperidinyl, 4-aminopiperidinyl, 2-propionylaminopiperazinyl, 2-iso
  • the benzoheterocyclic compounds of the present invention can be prepared by the following processes. ##STR5## wherein R, R 1 , R 2 , R 3 , A, B 1 and B 2 are the same as defined above.
  • the process of Reaction Scheme-1 is carried out by reacting a benzoheterocyclic compound (2) and a carboxylic acid compound (3) by the conventional amino bond producing reaction.
  • the amido bond producing reaction can be carried out under the conditions for the conventional amino bond producing reaction, for example,
  • a mixed acid anhydride process i.e. a process of reacting the carboxylic acid compound (3) with an alkyl halocarbonate ester to form a mixed acid anhydride and reacting the resultant with the amine compound (2),
  • an activated ester process i.e. a process of converting the carboxylic acid compound (3) into an activated ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and reacting the resultant with the amine compound (2),
  • a carbodiimide process i.e. a process of condensing the carboxylic acid compound (3) and the amine compound (2) in the presence of an activating agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc.,
  • the mixed acid anhydride used in the above mixed acid anhydride process (a) is obtained by the know Schotten-Baumann reaction, and the reaction product is used without isolating from the reaction mixture for the reaction with the amine compound (2) to give the desired compound (1) of the present invention.
  • the Schotten-Baumann reaction is usually carried out in the presence of a basic compound.
  • the basic compound is any conventional compounds used for the Schotten-Baumann reaction and includes, for example, organic basic compounds such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]-octane (DABCO), and inorganic basic compounds such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.
  • the reaction is usually carried out at a temperature from about -20° C. to about 100° C., preferably at 0° C. to about 50° C., for about 5 minutes to about 10 hours, preferably for 5 minutes to about 2 hours.
  • the reaction between the mixed acid anhydride thus obtained and the amine compound (2) is usually carried out at -20° C. to about 150° C., preferably at 10° C. to about 50° C., for 5 minutes to about 10 hours, preferably for 5 minutes to 5 hours.
  • the mixed acid anhydride process is usually carried out in a solvent.
  • the solvent may be any conventional solvents which are usually used in the mixed acid anhydride process and includes, for example, halogenated hydrocarbons (e.g. chloroform, dichloromethane, dichloroethane, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g.
  • diethyl ether diisopropyl ether, tetrahydrofuran, dimethoxyethane, etc.
  • esters e.g. methyl acetate, ethyl acetate, etc.
  • aprotic polar solvents e.g. N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoric triamide, etc.
  • a mixture of these solvents e.g. N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoric triamide, etc.
  • the alkyl halocarbonate ester used in the mixed acid anhydride process includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like.
  • the carboxylic acid compound (3), the alkyl halocarbonate ester and the amine compound (2) are usually used in each equimolar amount, but preferably, the alkyl halocarbonate ester and the carboxylic acid compound (3) are used each in an amount of about 1 to 1.5 mole to 1 mole of the amine compound (2).
  • the reaction is usually carried out in the presence of a basic compound in an appropriate solvent.
  • the basic compound is any conventional compounds and includes, for example, in addition to the basic compounds used for Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, and the like.
  • the solvent includes, for example, in addition to the solvents used in the mixed acid anhydride process, alcohols (e.g.
  • the amount of the amine compound (2) and the carboxylic acid halide is not critical, but the carboxylic acid halide is usually used at least in equimolar amount, preferably about 1 to 5 moles to 1 mole of the amine compound (2).
  • the reaction is usually carried out at a temperature from about -20° C. to about 180° C., preferably at 0° C. to about 150° C., for about 5 minutes to about 30 hours.
  • the amido bond producing reaction in Reaction Scheme-1 may also be carried out by reacting the carboxylic acid compound (3) and the amine compound (2) in the presence of a condensing agent such as phosphorus compounds (e.g. triphenylphosphine, diphenylphosphonyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoric azide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, etc.
  • the reaction is usually carried out in the presence of the solvent and the basic compound as used in the above reaction of the carboxylic acid halide and the amide compound (2) at a temperature from -20° C.
  • the condensing agent and the carboxylic acid compound (3) are used at least in equimolar amount, preferably about 1 to 2 moles, to 1 mole of the amine compound (2). ##STR6## wherein R A , R 1 , R 2 , R 3 , A, B 1 and B 2 are the same as defined above.
  • reaction of the compound (4) and the compound (5) is carried out in the same conditions as in the reaction of the compound (2) and the compound (3) in Reaction Scheme-1.
  • R, R 1 , R 3 , R 4 , R 5 , D, I, B 1 , A and B 2 are the same as defined above
  • R 2a is oxo group
  • R 2b is hydroxy group
  • R 2c is a group of the formula: --O--D(CO) I NR 4 R 5 (D, I, R 4 and R 5 are the same as defined above)
  • R 2d is a lower alkylidene group
  • R 2m is a lower alkoxy group or a lower alkenyloxy group
  • R 21 is a lower alkyl group or a lower alkenyl group
  • X is a halogen atom.
  • the reaction of converting the compound (1a) into the compound (1b) is carried out by subjecting the compound (1a) to reduction reaction.
  • the reduction reaction is preferably carried out by using a hydrogenation agent.
  • the hydrogenation agent includes, for example, lithium aluminum hydride, sodium borohydride, sodium trimethoxyborohydride, lithium borohydride, diborane, and the like.
  • the hydrogenation agent is used at least in an equimolar amount, preferably 1 mole to 15 moles, to 1 mole of the starting compound.
  • the reduction reaction is usually carried out in an appropriate solvent such as water, lower alcohols (e.g. methanol, ethanol, isopropanol, t-butanol, etc.), ethers (e.g.
  • tetrahydrofuran diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, diglyme, etc.
  • a temperature from -60° C. to 150° C., preferably at -30° C. to 100° C., for about 10 minutes to about 15 hours.
  • an anhydrous solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, and the like.
  • the reaction between the compound (1b) and the compound (6) is usually carried out in an appropriate inert solvent in the presence or absence of a basic compound.
  • the inert solvent includes, for example, aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride, etc.), lower alcohols (e.g.
  • the basic compound includes, for example, metal carbonates and metal hydrogen carbonates (e.g. sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), metal hydroxides (sodium hydroxide, potassium hydroxide, etc.), sodium hydride, potassium, sodium, sodium amide, metal alcoholates (e.g.
  • organic basic compounds e.g. pyridine, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]-undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and the like.
  • the amount of the compound (1b) and the compound (6) is not critical, but the compound (6) is used at least in an equimolar molar, preferably in an amount of 1 mole to 10 moles, to 1 mole of the compound (1b).
  • the reaction is usually carried out at a temperature from 0° C. to about 200° C., preferably 0° C. to about 170° C., for about 30 minutes to about 30 hours.
  • An alkali metal halide such as sodium iodide, potassium iodide, etc. may be added to this reaction system.
  • the reaction of converting the compound (1a) into the compound (1d) is carried out in an appropriate solvent in the presence of a phosphonium salt and a basic compound.
  • the phosphonium salt includes, for example, a phosphorus compound of the following formula.
  • R 9 is phenyl group
  • R 10 is hydrogen atom or a lower alkyl group
  • X is the same as defined above.
  • the basic compound includes, for example, inorganic bases such as sodium, potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc., and organic bases such as metal alcoholates (e.g. sodium methylate, sodium ethylate, potassium t-butoxide, etc.), alkyl lithium, aryl lithium or lithium amide (e.g.
  • the solvent may be any one which does not affect the reaction, and includes, for example, ethers (e.g. diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), aliphatic hydrocarbons (e.g.
  • n-hexane, heptane, cyclohexane, etc. aprotic polar solvents (e.g. pyridine, N,N-dimethylaniline, N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, etc.), alcohols (e.g. methanol, ethanol, isopropanol, etc.), and the like.
  • the reaction is usually carried out at a temperature from -80° C. to 150° C., preferably at a temperature from -80° to about 120° C., for 0.5 to about 15 hours.
  • reaction between the compound (1a) and the compound (21) can be carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6).
  • R, R 1 , A, B 1 and B 2 are the same as defined above, and R 2e is methylidene group.
  • the reaction of converting the compound (1e) into the compound (1f) is carried out by reacting with an oxidizing agent in the presence of a co-oxidizing agent in an appropriate solvent.
  • the solvent used in the reaction with an oxidizing agent includes, for example, ethers (e.g. pyridine, dioxane, tetrahydrofuran, diethyl ether, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), esters (e.g.
  • the co-oxidizing agent includes, N-oxides of organic amines such as pyridine N-oxide, N-ethyldiisopropylamine N-oxide, N-methylmorpholine N-oxide, trimethylamine N-oxide, triethylamine N-oxide, and the like.
  • the oxidizing agent includes, for example, osmium tetraoxide, and the like.
  • the oxidizing agent is used at least in equimolar amount, preferably in an amount of 1 mole to 5 moles, to 1 mole of the starting compound.
  • the reaction is carried out at a temperature from about -20° C. to about 150° C., preferably at a temperature from room temperature to about 100° C., for 1 to about 10 hours.
  • R, R 1 , R 3 , R 6 , R 7 , E, B 1 , A and B 2 are the same as defined above
  • R 2f is a lower alkoxycarbonyl-substituted lower alkyl group
  • R 2g is a carboxy-substituted lower alkyl group.
  • the hydrolysis of the compound (1g) is carried out in the presence of an acid or a basic compound in an appropriate solvent or without a solvent.
  • the solvent includes, for example, water, alcohols (e.g. methanol, ethanol, isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g. acetic acid, formic acid, etc.), or a mixture of these solvents.
  • the acid includes, for example, mineral acids (e.g.
  • the basic compound includes, for example, metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), and the like.
  • the reaction is usually carried out at a temperature from room temperature to about 200° C., preferably at a temperature from room temperature to about 150° C., for 10 minutes to about 25 hours.
  • the esterification of the compound (1h) is carried out by reacting the starting compound with an alcohol (e.g. methanol, ethanol, isopropanol, etc.) in the presence of a mineral acid (e.g. hydrochloric acid, sulfuric acid, etc.), or a halogenating agent (e.g. thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride) at a temperature from 0° C. to 150° C., preferably at a temperature from 50° C. to 100° C., for about 1 to about 10 hours.
  • an alcohol e.g. methanol, ethanol, isopropanol, etc.
  • a mineral acid e.g. hydrochloric acid, sulfuric acid, etc.
  • a halogenating agent e.g. thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichlor
  • reaction between the compound (1h) and the compound (8) is carried out under the same conditions as those of the reaction between the compound (2) and the compound (3) in Reaction Scheme-1.
  • R, R 1 , R 3 , A, B 1 , B 2 , R 4 , R 5 and D are the same as defined above
  • R 2h is a lower alkoxycarbonyl-substituted lower alkoxy group
  • R 2i is a carboxy-substituted lower alkoxy group.
  • the esterification of the compound (1k) is carried out under the same conditions as those of the esterification of the compound (1h) in Reaction Scheme-5.
  • R 2j is a hydroxy-substituted lower alkoxy group
  • R 11 is a lower alkyl group
  • R 2k is a lower alkylsulfonyloxy-substituted lower alkoxy group
  • R 2l is a phthalimide-substituted lower alkoxy group
  • M is an alkali metal such as potassium, sodium, etc.
  • R 2t is a group of the formula: --O--D--NR 4 R 5 (wherein D, R 4 and R 5 are the same as defined above), and R 2u is an imidazolyl-substituted lower alkoxy group.
  • reaction between the compound (1n) and the compound (10) is carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6) in Reaction Scheme-3.
  • reaction between the compound (1o) and the compound (11) is carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6) in Reaction Scheme-3.
  • the reaction of converting the compound (1p) into the compound (1q) is carried out by reacting the compound (1p) with hydrazine, or by hydrolysis of the compound (1p), in an appropriate solvent.
  • the solvent used in the reaction with hydrazine includes, for example, the solvents used for the reaction between the compound (2) and the compound (3) in Reaction Scheme-1 as well as water.
  • the reaction is usually carried out at a temperature from 0° C. to about 120° C., preferably from 0° C. to about 100° C., for 0.5 to about 5 hours.
  • Hydrazine is used at least in equimolar amount, preferably in an amount of 1 mole to 5 moles, to 1 mole of the compound (1p).
  • the above hydrolysis is carried out in the presence of an acid or a basic compound in an appropriate solvent or without a solvent.
  • the solvent includes, for example, water, alcohols (e.g. methanol, ethanol, isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g. acetic acid, formic acid, etc.), or a mixture of these solvents.
  • the acid includes, for example, mineral acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), and organic acids (e.g.
  • the basic compound includes, for example, metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), and the like.
  • the reaction is usually carried out at a temperature from room temperature to about 200° C., preferably at a temperature from room temperature to about 150° C., for 10 minutes to about 25 hours.
  • reaction between the compound (1o) and the compound (27), and the reaction between the compound (1o) and the compound (23) can be carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6) in Reaction Scheme-3.
  • R, R 1 , R 3 , A, B 1 , B 2 and X are the same as defined above
  • R 4a is a lower alkyl group, a cycloalkyl group or an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent
  • R 13 and R 14 are each hydrogen atom or a lower alkyl group
  • R 4b is a lower alkanoyl group
  • R 5a is hydrogen atom, a lower alkyl group, a lower alkanoyl group, a cycloalkyl group or an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent.
  • reaction between the compound (1r) and the compound (12) is carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6) in Reaction Scheme-3.
  • the reaction between the compound (1r) and the compound (13) is carried out in the presence of a reducing agent in an appropriate solvent or without a solvent.
  • the solvent includes, for example, water, alcohols (e.g. methanol, ethanol, isopropanol, etc.), acetonitrile, formic acid, acetic acid, ethers (e.g. dioxane, diethyl ether, diglyme, tetrahydrofuran, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), or a mixture thereof.
  • the reducing agent includes, for example, formic acid, alkali metal salts of fatty acids (e.g.
  • sodium formate, etc. hydrogenation agents (e.g. sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, etc.), catalytic reducing agents (e.g. palladium-black, palladium-carbon, platinum oxide, platinum black, Ranney nickel, etc.), and the like.
  • hydrogenation agents e.g. sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, etc.
  • catalytic reducing agents e.g. palladium-black, palladium-carbon, platinum oxide, platinum black, Ranney nickel, etc.
  • the reaction is usually carried out at a temperature from room temperature to about 200° C., preferably at about 50° C. to about 150° C., for about one to about 10 hours.
  • Formic acid is used in an excess amount to the compound (1r).
  • the reaction is usually carried out at a temperature from about -30° C. to about 100° C., preferably about 0° C. to about 70° C., for about 30 minutes to about 12 hours.
  • the hydrogenation agent is used in an amount of 1 mole to 20 moles, preferably in an amount of 1 mole to 6 moles, to 1 mole of the compound (1r).
  • the solvent is preferably ethers (e.g. diethyl ether, dioxane, tetrahydrofuran, diglyme, etc.) or aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.).
  • the reaction is usually carried out under atmospheric pressure to 20 atms of hydrogen, preferably, under atmospheric pressure to 10 atms of hydrogen, or in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, hydrazine hydrate, etc., at -30° C. to 100° C., preferably at 0° C. to 60° C., for about one to 12 hours.
  • the reducing agent is usually used in an amount of 0.1 to 40% by weight, preferably 1 to 20% by weight to the amount of the compound (1r).
  • the compound (13) is usually used at least in equimolar amount, preferably in equimolar to excess amount, to the compound (1r).
  • reaction between the compound (1r) and the compound (14) is carried out under the same conditions as those of the reaction between the compound (2) and the compound (3) in Reaction Scheme-1.
  • R, R 1 , R 3 , A, B 1 , B 2 , R 13 , R 14 , E, R 4b , I and X are the same as defined above
  • R 6a is a lower alkyl group or an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent
  • R 7a is hydrogen atom, a lower alkyl group, an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent, or a lower alkanoyl group.
  • reaction between the compound (1u) and the compound (25) is carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6) in Reaction Scheme-3.
  • reaction between the compound (1wa) or the compound (1wb) and the compound (15) is carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6) in Reaction Scheme-3.
  • R, R 1 , R 2a , R 3 , A, B 1 and B 2 are the same as defined above, and R 15 and R 16 are the same or different and are hydrogen atom, a lower alkyl group or a cycloalkyl group.
  • the reaction of converting the compound (1a) into the compound (1y) is carried out in the presence or absence of a dehydrating agent in an appropriate solvent or without a solvent.
  • the solvent includes, for example, alcohols (e.g. methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), aprotic polar solvents (e.g. dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc.), or a mixture of these solvents.
  • alcohols e.g. methanol, ethanol, isopropanol, etc.
  • aromatic hydrocarbons e.g. benzene, toluene, xylene, etc.
  • halogenated hydrocarbons e.
  • the dehydrating agent includes, for example, drying agents which are conventionally used for drying solvents (e.g. molecular sieve, etc.), mineral acids (e.g. hydrochloric acid, sulfuric acid, boron trifluoride, etc.), organic acids (e.g. p-toluenesulfonic acid, etc.), or a mixture thereof.
  • the reaction is usually carried out at a temperature from room temperature to 250° C., preferably at a temperature from about 50° C. to about 200° C., for one to about 48 hours.
  • the amount of the compound (16) is not critical, but it is used at least in equimolar amount, preferably 1 mole to excess amount, to 1 mole of the compound (1a).
  • the dehydrating agent is used in an excess amount when a drying agent is used, and when an acid is used as a dehydrating agent, it is used in a catalytic amount.
  • the subsequent reduction is carried out by various reduction reactions, for example, by catalytic hydrogenation in the presence of a catalyst in an appropriate solvent.
  • the solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane, cyclohexane, etc.), ethers (e.g. diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, diethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g. dimethylformamide, etc.), or a mixture of these solvents.
  • alcohols e.g. methanol, ethanol, isopropanol, etc.
  • hydrocarbons e.g. hexane, cyclohexane, etc.
  • ethers e.g
  • the catalyst is, for example, palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Ranney nickel, and the like.
  • the catalyst is usually used in an amount of 0.02 to 1 mole to 1 mole of the starting compound.
  • the reaction is usually carried out at a temperature from -20° C. to about 100° C., preferably at a temperature from 0° C. to about 70° C., under a pressure of 1 atm to 10 atms of hydrogen, for 0.5 to 20 hours.
  • the above mentioned conditions for reduction can be employed in the present reduction, but the reduction using a hydrogenation agent is more preferable.
  • the hydrogenation agent includes, for example, lithium aluminum hydride, sodium borohydride, diboran, etc., and is used at least in equimolar amount, preferably in an amount of 1 mole to 10 moles, to 1 mole of the compound (1a).
  • the reduction is carried out in an appropriate solvent such as water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ethers (e.g. tetrahydrofuran, diethyl ether, diglyme, etc.), dimethylformamide, or a mixture of these solvents, at a temperature of about -60° C.
  • anhydrous solvent such as diethyl ether, tetrahydrofuran, diglyme, etc., is preferably used.
  • the compound is converted into the compound (1y) wherein at least one of R 15 and R 16 is a lower alkyl group by reacting it with the compound (12) or the compound (13) under the same conditions as those of the reaction between the compound (1r) and the compound (12) or the compound (13) in Reaction Scheme-8.
  • the starting compound (3) or (4) can be prepared by the following processes. ##STR16## wherein R 17 is a lower alkyl group, and R A and A are the same as defined above.
  • reaction between the compound (17) and the compound (18) is carried out under the same conditions as those of the reaction between the compound (2) and the compound (3) in Reaction Scheme-1.
  • reaction between the compound (2) and the compound (19) is carried out under the same conditions as those of the reaction between the compound (2) and the compound (3) in Reaction Scheme-1.
  • the reduction of the compound (20) is carried out, for example, (i) by using a reducing catalyst in an appropriate solvent, or (ii) by using a mixture of a metal or a metal salt and an acid, or a mixture of a metal or a metal salt and an alkali metal hydroxide, sulfide, ammonium salt, etc., as a reducing agent in an inert solvent.
  • the solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane, cyclohexane, etc.), ethers (e.g. dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, etc.), or a mixture of these solvents.
  • alcohols e.g. methanol, ethanol, isopropanol, etc.
  • hydrocarbons e.g. hexane, cyclohexane, etc.
  • ethers e.g. dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl
  • the reducing catalyst includes, for example, palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Ranney nickel, and the like.
  • the catalyst is usually used in an amount of 0.02 to 1 mole to 1 mole of the starting compound.
  • the reaction is usually carried out at a temperature from about -20° C. to about 150° C., preferably at a temperature from 0° C. to 100° C., under a pressure of 1 atm to 10 atms of hydrogen, for 0.5 to about 10 hours.
  • An acid e.g. hydrochloric acid
  • a reducing agent a mixture of iron, zinc, tin or stannous chloride and a mineral acid (e.g. hydrochloric acid, sulfuric acid, etc.), or a mixture of iron, iron sulfide, zinc or tin and an alkali metal hydroxide (e.g. sodium hydroxide, etc.), sulfide (e.g. ammonium sulfide, etc.), aqueous ammonia, ammonium salt (e.g. ammonium chloride, etc.).
  • the inert solvent includes, for example, water, methanol, ethanol, dioxane, acetic acid, and the like.
  • the conditions for reduction can be selected according to the kinds of the reducing agent to be used.
  • the reaction is preferably carried out at a temperature from 0° C. to about 100° C., for 0.5 to about 10 hours.
  • the reducing agent may be used at least in equimolar amount, usually in an amount of 1 mole to 20 moles to 1 mole of the starting compound. ##STR18## wherein R 1 , R 2 , R 3 , R 18 , B 1 and B 2 are the same as defined above, p is 0, 1 or 2, R 18a is a lower alkoxycarbonyl group, and R 18b is carboxy group.
  • the hydrolysis of the compound (1B) is carried out under the same conditions as those of the hydrolysis of the compound (1g) in Reaction Scheme-5.
  • the esterification of the compound (1C) is carried out under the same conditions as those of the esterification of the compound (1h) in Reaction Scheme-5.
  • R 18c is a lower alkoxycarbonyl-substituted lower alkoxy group
  • R 18d is a carboxy-substituted lower alkoxy group
  • R 18e is a hydroxy-substituted lower alkoxy group
  • R 18f is a group of the formula: --O--E--CO--NR 19 R 20 (E, R 19 and R 20 are the same as defined above).
  • the hydrolysis of the compound (1D) is carried out under the same conditions as those of the hydrolysis of the compound (1g) in Reaction Scheme-5.
  • the esterification of the compound (1E) is carried out under the same conditions as those of the esterification of the compound (1h) in Reaction Scheme-5.
  • reaction of the compound (1E) with the compound (22) is carried out under the same conditions as those of the reaction between the compound (2) and the compound (3) in Reaction Scheme-1.
  • reaction of converting the compound (1D) into the compound (1F) is carried out under the same conditions as those of the reaction of converting the compound (1a) into the compound (1b) in Reaction Scheme-3.
  • R 1 , R 2 , R 18 , p, R 18e , R 11 , X, E, R 12 , R 19 , R 20 and M are the same as defined above.
  • reaction of the compound (1F) with the compound (10) is carried out under the same conditions as those of the reaction between the compound (1n) and the compound (10) in Reaction Scheme-7.
  • reaction of the compound (1H) with the compound (22) is carried out under the same conditions as those of the reaction between the compound (1n) and the compound (10) in Reaction Scheme-7.
  • reaction of the compound (1H) with the compound (11) is carried out under the same conditions as those of the reaction of the compound (1o) with the compound (11) in Reaction Scheme-7.
  • reaction of converting the compound (1J) into the compound (1K) is carried out under the same conditions as those of the reaction of converting the compound (1p) into the compound (1q) in Reaction Scheme-7.
  • reaction of the compound (1L) with the compound (12) is carried out under the same conditions as those of the reaction between the compound (1r) and the compound (12) in Reaction Scheme-8.
  • the reaction of the compound (1L) with the compound (13) is carried out under the same conditions as those of the reaction between the compound (1r) and the compound (13) in Reaction Scheme-8.
  • R 2m is a hydroxy-substituted lower alkyl group
  • R 2n is a lower alkylsuflonyloxy-substituted lower alkyl group
  • R 2o is a group of the formula: --E--NR 6 R 7 (E, R 6 and R 7 are the same as defined above)
  • R 2 P is a phthalimide-substituted lower alkyl group
  • R 2q is an imidazolyl-substituted lower alkyl group
  • R 2r is a 1,2,4-triazolyl-substituted lower alkyl group
  • R 2s is a lower alkanoyloxy-substituted lower alkyl group.
  • the reaction of converting the compound (1N) into the compound (1O) is carried out under the same conditions as those of the reaction of converting the compound (1m) into the compound (1n) in Reaction Scheme-7.
  • the reaction between the compound (1P) and the compound (8), the reaction of the compound (1P) with the compound (23) and the reaction of the compound (1P) with the compound (24) are carried out under the same conditions as those of the reaction of the compound (1n) with the compound (10) in Reaction Scheme-7.
  • reaction of the compound (1P) with the compound (11) is carried out under the same conditions as those of the reaction of the compound (1o) with the compound (11) in Reaction Scheme-7.
  • reaction of converting the compound (1R) into the compound (1S) is carried out under the same conditions as those of the reaction of converting the compound (1p) into the compound (1s) in Reaction Scheme-7.
  • the reaction of converting the compound (1O) into the compound (1V) is carried out by lower-alkanoylating the compound (1O) by using a compound of the formulae: (R 22 ) 2 O (26) or R 22 X (27) [wherein R 22 is a lower alkanoyl group, and X are the same as defined above].
  • This lower-alkanoylating reaction is carried out in the presence or absence of a basic compound.
  • the basic compound includes, for example, alkali metals (e.g. sodium, potassium, etc.), hydroxides, carbonates, hydrogen carbonates of these alkali metals, or organic bases such as N,N-dimethylaminopyridine, pyridine, piperidine, and the like.
  • the reaction can proceed either without a solvent, or in a solvent.
  • the solvent includes, for example, ketones (e.g. acetone, methyl ethyle ketone, etc.), ethers (e.g. diethyl ether, dioxane, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), water, pyridine, and the like.
  • the compounds (7) and (8) are used at least in equimolar amount to the starting compound, but they are preferably used in an amount of 1 mole to excess amount to 1 mole of the starting compound.
  • the above reaction is carried out at a temperature from 0° to 200° C., preferably at about 0° C. to about 150° C., for 5 minutes to about 5 days.
  • the compound (1) wherein the groups of R 6 and R 7 form a piperazine ring being substituted by a lower alkoxycarbonyl group at 4-position can be hydrolyzed under the same conditions as those of the hydrolysis of the compound (1g) in Reaction Scheme-5, and converted into the compound (1) wherein the substituent at 4-position of said piperazine ring is hydrogen atom.
  • the compound (1) wherein both R 2 and R 3 are a lower alkoxy group, and they bond at the same position can be hydrolyzed under the same conditions as those of the hydrolysis of the compound (1g) in Reaction Scheme-5, and converted into the compound (1) wherein R 2 is oxo group.
  • the compounds having an acidic group can easily be converted into salts by treating with a pharmaceutically acceptable basic compound.
  • the basic compound includes, for example, metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, etc.), alkali metal carbonates or hydrogen carbonates (e.g. sodium carbonate, sodium hydrogen carbonate, etc.) and alkali metal alcoholates (e.g. sodium methylate, potassium ethylate, etc.).
  • the compounds having a basic group can easily be converted into acid addition salts thereof by treating with a pharmaceutically acceptable acid.
  • the acid includes, for example, inorganic acids (e.g.
  • the compounds (1) of the present invention include stereoisomers and optical isomers, and these isomers are also useful as vasopressin antagonist.
  • the compounds of the present invention thus obtained can easily be isolated and purified by conventional isolation methods.
  • the isolation methods are, for example, distillation method, recrystallization method, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography, extraction with a solvent, and the like.
  • the desired compounds (1) of the present invention and salts thereof are useful as a vasopressin antagonist, and are used in the form of a conventional pharmaceutical preparation.
  • the preparation is prepared by using conventional diluents or carriers such as fillers, thickening agents, binders, wetting agent, disintegrators, surfactants, lubricants, and the like.
  • the pharmaceutical preparations can be selected from various forms in accordance with the desired utilities, and the representative forms are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), and the like.
  • carriers such as vehicles (e.g.
  • lactose white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.
  • binders e.g. water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrators e.g.
  • dry starch sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, starches, lactose, etc.), disintegration inhibitors (e.g. white sugar, stearin, cacao butter, hydrogenated oils, etc.), absorption promoters (e.g. quaternary ammonium base, sodium laurylsulfate, etc.), wetting agents (e.g. glycerin, starches, etc.), adsorbents (e.g.
  • the tablets may also be in the form of a conventional coated tablet, such as sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film coating tablets, or double or multiple layer tablets.
  • the carriers include vehicles (e.g. glucose, lactose, starches, cacao butter, hydrogenated vegetable oils, kaolin, talc, etc.), binders (e.g.
  • the carriers include, for example, polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides, and the like.
  • Capsules can be prepared by charging a mixture of the compound of the present invention and the above carriers into hard gelatin capsules or soft capsules in usual manner.
  • the solutions, emulsions and suspensions are sterilized and are preferably made isotonic with the blood.
  • the pharmaceutical preparations may also be incorporated with sodium chloride, glucose, or glycerin in an amount sufficient to make them isotonic, and may also be incorporated with conventional solubilizers, buffers, anesthetizing agents.
  • the pharmaceutical preparations may optionally be incorporated with coloring agent, preservatives, perfumes, flavors, sweeting agents, and other medicaments, if required.
  • the amount of the desired compound of the present invention to be incorporated into the vasopressin antagonist is not specified but may be selected from a broad range, but usually, it is preferably in the range of 1 to 70 by weight, more preferably 5 to 50% by weight.
  • the vasopressin antagonist containing as an active ingredient the compounds (1) of the present invention and a salt thereof may be administered in any method, and suitable method for administration may be determined in accordance with various forms of preparations, ages, sexes and other conditions of the patients, the degree of severity of diseases, and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally.
  • the injections are intravenously administered alone or together with a conventional auxiliary liquid (e.g. glucose, amino acid solutions), and further are optionally administered alone in intramuscular, intracutaneous, subcutaneous, or intraperitoneal route, if required. Suppositories are administered in intrarectal route.
  • a conventional auxiliary liquid e.g. glucose, amino acid solutions
  • the dosage of the vasopressin antagonist of the present invention may be selected in accordance with the usage, ages, sexes and other conditions of the patients, the degree of severity of the diseases, and the like, but it is usually in the range of about 0.6 to 50 mg of the active compound of the present invention per 1 kg of body weight of the patient per day.
  • the active compound is preferably contained in an amount of about 10 to about 1000 mg per the dosage unit.
  • the present invention is illustrated in more detail by the following Preparations of vasopressin antagonist, Reference Examples of processes for preparing the starting compounds to be used for preparing the desired compounds of the present invention, and Examples of processes for preparing the desired compounds, and Experiments of the activities of the desired compounds of the present invention.
  • Film coated tablets are prepared from the following compounds.
  • the active compound of the present invention Avicel, corn starch and magnesium stearate are mixed and kneaded and the mixture is tabletted using a conventional pounder (R 10 mm) for sugar coating.
  • the tablets thus obtained are coated with a film coating agent consisting of hydroxypropyl methylcellulose, polyethylene glycol-6000, castor oil and ethanol to give film coated tablets.
  • Tablets are prepared from the following components.
  • the active compound of the present invention citric acid, lactose, dicalcium phosphate, Pullonic F-68 and sodium laurylsulfate are mixed.
  • the mixture is screened with No. 60 screen and is granulated with an alcohol solution containing polyvinylpyrrolidone, Carbowax 1500 and 6000. If required, an alcohol is added thereto so that the powder mixture is made a paste-like mass.
  • Corn starch is added to the mixture and the mixture is continuously mixed to form uniform particles.
  • the resulting particles are passed through No. 10 screen and entered into a tray and then dried in an oven at 100° C. for 12 to 14 hours.
  • the dried particles are screened with No. 16 screen and thereto are added dry sodium laurylsulfate and dry magnesium stearate, and the mixture is tabletted to form the desired shape.
  • the core tablets thus prepared are vanished and dusted with talc in order to guard from wetting. Undercoating is applied to the core tablets. In order to administer the tablets orally, the core tablets are vanished several times. In order to give round shape and smooth surface to the tablets, further undercoating and coating with lubricant are applied thereto. The tablets are further coated with a coloring coating material until the desired colored tablets are obtained. After drying, the coated tablets are polished to obtain the desired tablets having uniform gloss.
  • An injection preparation is prepared from the following components.
  • the above parabens, sodium metabisulfite and sodium chloride are dissolved with stirring in distilled water of half volume of the above with stirring at 80° C.
  • the solution thus obtained is cooled to 40° C., and the active compound of the present invention and further polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution.
  • To the solution is added distilled water for injection to adjust to the desired volume, and the solution is sterilized by filtering with an appropriate filter paper to give an injection preparation.
  • 6-nitronicotinic acid 3.5 g
  • thionyl chloride 50 ml
  • the mixture is refluxed for three hours, and evaporated to remove thionyl chloride to give 6-nitronicotinoyl chloride, which is added with stirring to a solution of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzazepine (3.4 g) in pyridine (50 ml) under ice-cooling.
  • the mixture is stirred at room temperature overnight.
  • To the reaction mixture is added water, and the mixture is extracted with ethyl acetate.
  • the extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent.
  • the residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-methylamino-1-[5-(2-methylbenzoylamino)thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.93 g) as white powder.
  • Example 83 Using the suitable starting compounds, there is obtained the compound of Example 83 in the same manner as in Example 150.
  • the mixture is extracted with dichloromethane, and the extract is washed successively with diluted aqueous sodium hydroxide solution and water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent.
  • the residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-1- ⁇ 6-[2-(4-methyl-1-piperazinyl)-carbonyl methoxybenzoylamino]nicotinoyl ⁇ -2,3,4,5-tetrahydro-1H-benzazepine (390 mg) as white powder.
  • Example 91 Using the suitable starting compounds, there is obtained the compound of Example 91 in the same manner as in Example 156.
  • Example 123 Using the suitable starting compounds, there is obtained the compound of Example 123 in the same manner as in Example 158.
  • Example 124 Using the suitable starting compounds, there is obtained the compound of Example 124 in the same manner as in Example 159.
  • Example 134 Using the suitable starting compounds, there is obtained the compound of Example 134 in the same manner as Example 160.
  • Example 141 Using the suitable starting compounds, there is obtained the compound of Example 141 in the same manner as in Example 162.
  • Example 142 Using the suitable starting compounds, there is obtained the compound of Example 142 in the same manner as in Example 163.
  • rat liver plasma membrane preparations prepared according to Ichihara's method [cf: Akira Ichihara, J. Bio. Chem., 258, 9283 (1983)]
  • the plasma membrane (50000 dpm, 2 ⁇ 10 -10 M) of [ 3 H]-Arg-vasopressin and a test compound (60 ⁇ g, 10 -8 to 10 -4 M) are incubated at 37° C. for 10 minutes in 100 mM Tris-HCl buffer (pH: 8.0) (250 ⁇ l) containing 5 mM MgCl 2 , 1 mM EDTA and 0.1% BSA.
  • IC 50 value is the concentration of the test compound required to achieve the inhibitory effect in the rate of 50%.
  • rat kidney plasma membrane preparations prepared according to O. Hechter's method [cf: J. Bio. Chem., 253, 3211 (1978)]
  • the plasma membrane (100000 dpm, 4 ⁇ 10 -10 M) of [ 3 H]-Arg-vasopressin and a test compound 0.6 mg, 10 -10 to 10 -5 M) are incubated at 4° C. for 3 hours in 100 mM Tris-HCl buffer (pH: 8.0) (250 ⁇ l) containing 5 mM MgCl 2 , 1 mM EDTA and 0.1% BSA.
  • IC 50 value is the concentration of the test compound required to achieve the inhibitory effect in the rate of 50%.
  • uterine muscle is taken out from a rat which has previously been injected subcutaneously with diethylstilbestrol the day before, and homogenized, which is used as a membrane preparation.
  • the membrane preparation (0.2 mg), [ 3 H]-oxytocin (100000 dpm, 10 -9 M), a test compound (10 -9 -10 -5 M) are incubated at 25° C. for one hour in 100 mM Tris-HCl buffer (pH 8.0, 250 ⁇ l) containing a 5 mM MgCl 2 , 1 mM MEDTA and 0.1% BSA.
  • the mixture is filtered through the glass filter (GF/B) so as to separate the membrane preparation binding with [ 3 H]-oxytocin, and then, washed twice with the buffer (5 ml).
  • This glass filter is put into a vial and mixed with Aquasole (liquid scintillation cocktail).
  • Aquasole liquid scintillation cocktail
  • the amount of [ 3 H]-oxytocin binding with the membrane is measured by liquid scintillation counter.
  • the rate of the inhibitory effect of the test compound is estimated according to the following equation.
  • IC 50 value is the concentration of the test compound required to achieve the inhibitory rate in the rate of 50%.

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Abstract

Novel benzoheterocyclic compound of the formula (1): ##STR1## and pharmaceutically acceptable salts thereof, which show excellent anti-vasopressin activity and oxytocin antagonistic activity, and are useful as a vasopressin antagonist or oxytocin antagonist.

Description

DESCRIPTION
1. Technical Field
The invention relates to novel benzoheterocyclic compounds which are useful as medicines.
2. Background Art
Various benzoheterocyclic compounds analogous to the compounds of the present invention have been known to have anti-vasopressin activities in European Patent Publication 0382185 (published on Aug. 16, 1990), WO 91/05549 (published on May 2, 1991), and EP-A-0470514 (published on Feb. 12, 1992). These known compounds are similar to the compounds of the present invention in the benzoheterocyclic nucleus of the chemical structure but are different from the compounds of the present invention in the substituent at 1-position and in the anti-vasopressin activities to some extent.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide benzoheterocyclic compounds of the formula (1): ##STR2## wherein R1 is hydrogen atom or a halogen atom,
R2 is hydrogen atom, oxo group, a lower alkylidene group, hydroxy group, a lower alkoxy group, a lower alkenyloxy group, a hydroxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkylsulfonyloxy-substituted lower alkoxy group, a phthalimide-substituted lower alkoxy group, a hydroxy-substituted lower alkyl group, a group of the formula: --O--D--(CO)I NR4 R5 (wherein D is a lower alkylene group, I is 0 or 1, R4 and R5 are the same or different and are hydrogen atom, a lower alkyl group, a lower alkanoyl group, a cycloalkyl group, or an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent, or R4 and R5 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group which may be intervened or not with a nitrogen atom, an oxygen atom or a sulfur atom, wherein said heterocyclic group may optionally be substituted by a lower alkyl group or a lower alkanoyl group), a group of the formula: --E--(CO)I NR6 R7 (wherein I is the same as defined above, E is a lower alkylene group, R6 and R7 are the same or different and are hydrogen atom, a lower alkyl group, an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent, or a lower alkanoyl group, or R6 and R7 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group which may be intervened or not with a nitrogen atom, an oxygen atom or a sulfur atom, wherein said heterocyclic group may optionally be substituted by a lower alkyl group, a lower alkanoyl group or a lower alkoxycarbonyl group), a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl-substituted lower alkyl group, an amino which may optionally be substituted by a lower alkyl group or a cycloalkyl group, a carboxy-substituted lower alkyl group, a lower alkylsulfonyloxy-substituted lower alkyl group, a phthalimide-substituted lower alkyl group, an imidazolyl-substituted lower alkyl group, a 1,2,4-triazolyl-substituted lower alkyl group, an amino-substituted lower alkanoyloxy group which may optionally have a lower alkyl substituent, or an imidazolyl-substituted lower alkoxy group,
R3 is hydrogen atom, a lower alkoxy group or a hydroxy-substituted lower alkyl group,
B1 and B2 are each methylene group or a group of the formula: --NR8 -- (wherein R8 is hydrogen atom or a lower alkyl group),
A is a 5- or 6-membered unsaturated heterocyclic residue having 1 to 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
R is a group of the formula: --NHRA or a group of the formula: ##STR3## wherein RA is a group of the formula: ##STR4## [wherein m is an integer of 1 to 3, R18 is hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, nitro group, a lower alkoxycarbonyl group, carboxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a hydroxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkylsulfonyloxy-substituted lower alkoxy group, a phthalimide-substituted lower alkoxy group, or a group of the formula: --O--E--(CO)I NR19 R20 (wherein E and I are the same as defined above, R19 and R20 are the same or different and are hydrogen atom or a lower alkyl group, or R19 and R20 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group which may be intervened or not with a nitrogen atom or an oxygen atom, wherein said heterocyclic group may optionally be substituted by a lower alkyl group, or an amino group which may optionally be substituted by a lower alkanoyl group)], thienylcarbonyl group, a cycloalkylcarbonyl group or a phenyl-lower alkanoyl group which may optionally have a lower alkyl substituent on the phenyl ring, or a salt thereof.
The compounds of the formula (1) of the present invention and salts thereof show excellent vasopressin antagonistic activities, for examples, vasodilating activity, hypotensive activity, activity for inhibiting saccharide release in liver, activity for inhibiting growth of mesangium cells, water diuretic activity, platelet agglutination inhibitory activity, inhibitory activity for vomiting, and hence, they are useful as vasodilators, hypotensive agents, water diuretics, platelet agglutination inhibitor, etc., and are used in the prophylaxis or treatment of hypertension, edema, ascites, heart failure, renal function disorder, vasopressin parasecretion syndrome (SIADH), hepatocirrhosis, hyponatremia, hypokalemia, diabetic, circulation disorder, motion sickness, and the like. In addition, the compounds of the present invention and salts thereof show oxytocin antagonistic activities, for example, inhibitory effect on uterine smooth muscle constriction, inhibitory effect on milk secretion, inhibitory effect on synthesis and secretion of prostaglandin, and vasodilation activity, and hence, are useful in the protection or treatment of oxytocin-associated diseases, especially premature delivery, dysmenorrhea, endometritis, or in stopping labor preparatory to Caesarian delivery. Besides, the compounds of the present invention and salts thereof are characteristic in less side effects, and in prolonged action for a long time in living body.
Each group in the above formula (1) specifically includes the following groups.
The "lower alkoxy group" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, and the like.
The "lower alkyl group" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like.
The "halogen atom" includes fluorine atom, chlorine atom, bromine atom, and iodine atom.
The "lower alkylene group" includes a straight chain or branched chain alkylene group having 1 to 6 carbon atoms, for example, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene, and the like.
The "hydroxy-substituted lower alkoxy group" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by 1 to 3 hydroxy groups, for example, hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxyethoxy, 4-hydroxybutoxy, 3,4-dihydroxybutoxy, 1,1-dimethyl-2-hydroxyethoxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy, 2-methyl-3-hydroxypropoxy, 2,3,4-trihydroxybutoxy, and the like,
The "lower alkanoyl group" includes a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, t-butylcarbonyl, hexanoyl, and the like.
The "carboxy-substituted lower alkyl group" includes a carboxyalkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, carboxymethyl, 2-carboxylethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1,1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyl, and the like.
The "5- or 6-membered saturated heterocyclic group which is formed by combining the groups R4 and R5, or the groups of R6 and R7 with the nitrogen atom to which they bond, which may be intervened or not with nitrogen atom, oxygen atom or sulfur atom" includes pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, and the like.
The "above mentioned heterocyclic group which is substituted by a lower alkyl group or a lower alkanoyl group" includes the above mentioned heterocyclic groups which are substituted by 1 to 3 groups selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2 -propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 3-methylthiomorpholino, 4-hexylpiperazinyl, 4-acetylpiperazinyl, 4-formyl-3-methylpiperazinyl, 3-propionylpyrrolidinyl, 2-butyrylpyrrolidinyl, 4-pentanoylpiperidinyl, 3-hexanoylmorpholino, 3,4,5-triacetylpiperidinyl, and the like.
The "above mentioned heterocyclic groups substituted by a lower alkyl group, a lower alkanoyl group or a lower alkoxycarbonyl group" includes the above mentioned heterocyclic groups substituted by 1 to 3 groups selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms and a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 3-methylthiomorpholino, 4-hexylpiperazinyl, 4-acetylpiperazinyl, 4-formyl-3-methylpiperazinyl, 3-propionylpyrrolidinyl, 2-butyrylpyrrolidinyl, 4-pentanoylpiperidinyl, 3-hexanoylmorpholino, 3,4,5-triacetylpiperidinyl, 4-t-butoxycarbonylpiperazinyl, 3-methoxycarbonylpyrrolidinyl, 2-ethoxycarbonylpyrrolidinyl, 4-propoxycarbonylpiperidinyl, 3-pentyloxycarbonylmorpholino, 3-hexyloxycarbonylpiperidinyl, 3,5-dimethyl-4-t-butoxycarbonylpiperazinyl, 3-acetyl-4-t-butoxycarbonylpiperazinyl, and the like.
The "5- or 6-membered unsaturated heterocyclic residue having 1 to 2 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom" includes imidazolyl, pyrrolyl, imidazolinyl, pyridyl, primidyl, oxazolyl, pyrazolyl, pyrazolinyl, thiazolyl, thiazolinyl, thienyl, furyl, pyranyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrrolinyl, and the like.
The "cycloalkylcarbonyl group" includes a cycloalkylcarbonyl group having 3 to 8 carbon atoms in the cycloalkyl moiety, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, and the like.
The "phenyl-lower alkanoyl wherein the phenyl moiety may optionally have a lower alkyl substituent" includes phenylalkanoyl groups wherein the phenyl ring may optionally have 1 to 3 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and the alkanoyl moiety is a straight chain or branched chain alkanoyl group having 2 to 6 carbon atoms, for example, phenylacetyl, 3-phenylpropionyl, 2-phenylpropionyl, 4-phenylbutyryl, 2,2-dimethyl-3-phenylpropionyl, 5-phenylpentanoyl, 6-phenylhexanoyl, (2-methylphenyl)acetyl, (3-methylphenyl)acetyl, (4-methylphenyl)acetyl, 2-(2-ethylphenyl)propionyl, 3-(3-isopropylphenyl)propionyl, 4-(3-butylphenyl)butyryl, 2,2-dimethyl-3-(4-pentylphenyl)propionyl, 5-(4-hexylphenyl)pentanoyl, 6-(3,4-dimethylphenyl)hexanoyl, (3,4,5-trimethylphenyl)acetyl, and the like.
The "hydroxy-substituted lower alkyl group" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which has 1 to 3 hydroxy substituents, for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyethyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl, 6-hydroxyhexyl, 2-methyl-3-hydroxypropyl, 2,3,4-trihydroxybutyl, and the like.
The "lower alkylidene group" includes a straight chain or branched chain alkylidene group having 1 to 6 carbon atoms, for example, methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene, hexylidene, and the like.
The "lower alkoxycarbonyl-substituted lower alkoxy group" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, methoxycarbonylmethoxy, 3-methoxycarbonylpropoxy, ethoxycarbonylmethoxy, 3-ethoxycarbonylpropoxy, 4-ethoxycarbonylbutoxy, 5-isopropoxycarbonylpentyloxy, 6-propoxycarbonylhexyloxy, 1,1-dimethyl-2-butoxycarbonylethoxy, 2-methyl-3-t-butoxycarbonylpropoxy, 2-pentyloxycarbonylethoxy, hexyloxycarbonylmethoxy, and the like.
The "carboxy-substituted lower alkoxy group" includes a carboxyalkoxy group wherein the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, carboxymethoxy, 2-carboxyethoxy, 1-carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy, 1,1-dimethyl-2-carboxyethoxy, 2-methyl-3-carboxypropoxy, and the like.
The "lower alkylsulfonyloxy-substituted lower alkoxy group" includes an alkylsulfonyloxyalkoxy group wherein the alkylsulfonyloxy moiety is a straight chain or branched chain alkylsulfonyloxy group having 1 to 6 carbon atoms and the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methylsulfonyloxymethoxy, 3-methylsulfonyloxypropoxy, ethylsulfonyloxymethoxy, 3-ethylsulfonyloxypropoxy, 2-methylsulfonyloxyethoxy, 4-ethylsulfonyloxybutoxy, 5-isopropylsulfonyloxypentyloxy, 6-propylsulfonyloxyhexyloxy, 1,1-dimethyl-2-butylsulfonyloxyethoxy, 2-methyl-3-t-butylsulfonyloxypropoxy, 2-pentylsulfonyloxyethoxy, hexylsulfonyloxymethoxy, and the like.
The "phthalimide-substituted lower alkoxy": group includes a phthalimide-substituted alkoxy group wherein the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, phthalimidomethoxy, 2-phthalimidoethoxy, 1-phthalimidoethoxy, 3-phthalimidopropoxy, 4-phthalimidobutoxy, 5-phthalimidopentyloxy, 6-phthalimidohexyloxy, 1,1-dimethyl-2-phthalimidoethoxy, 2-methyl-3-phthalimidopropoxy, and the like.
The "lower alkoxycarbonyl-substituted lower alkyl group" includes an alkoxycarbonylalkyl group wherein the alkoxycarbonyl moiety is a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety and the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methoxycarbonylmethyl, 3-methoxycarbonylpropyl, ethoxycarbonylmethyl, 3-ethoxycarobnylpropyl, 4-ethoxycarbonylbutyl, 5-isopropoxycarbonylpentyl, 6-propoxycarbonylhexyl, 1,1-dimethyl-2-butoxycarbonylethyl, 2-methyl-3-t-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl, hexyloxycarbonylmethyl, and the like.
The "amino which may optionally have 1 to 2 substituents of a lower alkyl group or a cycloalkyl group" includes an amino which may optionally be substituted by a straight chain or branched chain alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, for example, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, dicyclopropylamino, dicyclobutylamino, dicyclopentylamino, dicyclohexylamino, dicycloheptylamino, dicyclooctylamino, N-methyl-N-cyclopropylamino, N-ethyl-N-cyclopropylamino, N-methyl-N-cyclopentylamino, N-ethyl-N-cyclohexylamino, and the like.
The "lower alkenyloxy group" includes a straight chain or branched chain alkenyloxy group having 2 to 6 carbon atoms, for example, vinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 1-methylallyloxy, 2-pentenyloxy, 2-hexenyloxy, and the like.
The "cycloalkyl group" includes cycloalkyl groups having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, and the like.
The "amino-substituted lower alkyl group which may optionally have a lower alkyl substituent" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by an amino group optionally having 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminoethyl, 2-diethylaminoethyl, 2-dimethylaminoethyl, (N-ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)ethyl, and the like.
The "lower alkoxycarbonyl group" includes a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyoxycarbonyl, and the like.
The "lower alkanoyloxy-substituted lower alkyl group" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkanoyloxy group having 2 to 6 carbon atoms, for example, acetyloxymethyl, 2-acetyloxyethyl, 3-propionyloxypropyl, 4-butyryloxybutyl, 5-isobutyryloxypentyl, 1,1-dimethyl-2-pentanoyloxyethyl, 5-hexanoyloxypentyl, 6-acetyloxyhexyl, 2-methyl-3-acetyloxypropyl, and the like.
The "lower alkylsulfonyloxy-substituted lower alkyl group" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkylsulfonyloxy group having 1 to 6 carbon atoms, for example, methylsulfonyloxymethyl, 3-methylsulfonyloxypropyl, ethylsulfonyloxymethyl, 3-ethylsulfonyloxypropyl, 2-methylsulfonyloxyethyl, 4-ethylsulfonyloxybutyl, 5-isopropylsulfonyloxypentyl, 6-propylsulfonyloxyhexyl, 1,1-dimethyl-2-butylsulfonyloxyethyl, 2-methyl-3-t-butylsulfonyloxypropyl, 2-pentylsulfonyloxyethyl, hexylsulfonyloxymethyl, and the like.
The "phthalimide-substituted lower alkyl group" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a phthalimide group, for example, phthalimidomethyl, 2-phthalimidoethyl, 1-phthalimidoethyl, 3-phthalimidopropyl, 4-phthalimidobutyl, 5-phthalimidopentyl, 6-phthalimidohexyl, 1,1-dimethyl-2-phthalimidoethyl, 2-methyl-3-phthalimidopropyl, and the like.
The "imidazolyl-substituted lower alkyl group" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by an imidazolyl group, for example, (1-imidazolyl)methyl, 2-(1-imidazolyl)ethyl, 1-(2-imidazolyl)ethyl, 3-(4-imidazolyl)propyl, 4-(5-imidazolyl)butyl, 5-(1 -imidazolyl)pentyl, 6-(2-imidazolyl)hexyl, 1,1-dimethyl-2-(1-imidazolyl)ethyl, 2-methyl-3-(1-imidazolyl)propyl, and the like.
The "1,2,4-triazolyl-substituted lower alkyl group" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a 1,2,4-triazolyl group, for example, (1,2,4-triazol-1-yl)methyl, 2-(1,2,4-triazol-1-yl)ethyl, 1-(1,2,4-triazol-1-yl)ethyl, 3-(1,2,4-triazol-3-yl)propyl, 4-(1,2,4-triazol-5-yl)butyl, 5-(1,2,4-triazol- 1 -yl)pentyl, 6-(1,2,4-triazol-3-yl)hexyl, 1,1-dimethyl-2-(1,2,4-triazol-5-yl)ethyl, 2-methyl-3-(1,2,4-triazol-1-yl)propyl, and the like.
The "imidazolyl-substituted lower alkoxy group" includes a straight chain or branched chain alkoxyl group having 1 to 6 carbon atoms which is substituted by an imidazolyl group, for example, (1-imidazolyl)methoxy, 2-(1-imidazolyl)ethoxy, 1-(2-imidazolyl)ethoxy, 3-(4-imidazolyl)propoxy, 4-(5-imidazolyl)butoxy, 5-(1 -imidazolyl)pentyloxy, 6-(2-imidazolyl)hexyloxy, 1,1-dimethyl-2-(1-imidazolyl)ethoxy, 2-methyl-3-(1-imidazolyl)propoxy, and the like.
The "amino-substituted lower alkanoyloxy group which may optionally have a lower alkyl substituent" includes a straight chain or branched chain alkanoyloxy group having 2 to 6 carbon atoms which is substituted by an amino group optionally being substituted by 1 to 2 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms, for example, 2-aminoacetyloxy, 3-aminopropionyloxy, 2-aminopropionyloxy, 4-aminobutyryloxy, 5-aminopentanoyloxy, 6-aminohexanoyloxy, 2,2-dimethyl-3-aminopropionyloxy, 2-methyl-3-aminopropionyloxy, 2-methylaminoacetyloxy, 2-ethylaminopropionyloxy, 3-propylaminopropionyloxy, 3-isopropylaminopropionyloxy, 4-butylaminobutyryloxy, 5-pentylaminopentanoyloxy, 6-hexylaminohexanoyloxy, 2-dimethylaminoacetyloxy, 2-diethylaminoacetyloxy, 2-(N-ethyl-N-propylamino)acetyloxy, 3-(N-methyl-N-hexylamino)propionyloxyl, and the like.
The "an amino group which may optionally have a lower alkanoyl substituent" includes an amino group which may optionally have a substituent of a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, amino, acetylamino, propionylamino, isopropionylamino, butyrylamino, pentanoylamino, hexanoylamino, formylamino, and the like.
The "5- or 6-membered saturated heterocyclic group which is formed by combining the groups R19 and R20 with the nitrogen atom to which they bond, which may be intervened or not with nitrogen atom or oxygen atom" includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, and the like.
The "above mentioned heterocyclic groups which are substituted by an amino group optionally being substituted by a lower alkyl group or a lower alkanoyl group" includes, for example, the above mentioned heterocyclic groups which are substituted by 1 to 3 amino groups optionally being substituted by a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, or a straight chain or branched chain alkanoyl group having 1 to carbon atoms, for example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 3-methyl-4-acetylaminopiperidinyl, 4-hexylpiperazinyl, 4-acetylaminopiperidinyl, 4-aminopiperidinyl, 2-propionylaminopiperazinyl, 2-isopropionylaminopyrrolidinyl, 3-butyrylaminomorpholino, 4-methyl-3-acetylaminopiperazinyl, 3-pentanoylaminopiperazinyl, 4-hexanoylaminopiperidinyl, and the like.
The benzoheterocyclic compounds of the present invention can be prepared by the following processes. ##STR5## wherein R, R1, R2, R3, A, B1 and B2 are the same as defined above.
The process of Reaction Scheme-1 is carried out by reacting a benzoheterocyclic compound (2) and a carboxylic acid compound (3) by the conventional amino bond producing reaction. The amido bond producing reaction can be carried out under the conditions for the conventional amino bond producing reaction, for example,
(a) a mixed acid anhydride process, i.e. a process of reacting the carboxylic acid compound (3) with an alkyl halocarbonate ester to form a mixed acid anhydride and reacting the resultant with the amine compound (2),
(b) an activated ester process, i.e. a process of converting the carboxylic acid compound (3) into an activated ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and reacting the resultant with the amine compound (2),
(c) a carbodiimide process, i.e. a process of condensing the carboxylic acid compound (3) and the amine compound (2) in the presence of an activating agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc.,
(d) other processes, i.e. a process of converting the carboxylic acid compound (3) into a carboxylic anhydride by treating it with a dehydrating agent such as acetic anhydride, and reacting the resultant with the amine compound (2); a process of reacting an ester of the carboxylic acid compound (3) with a lower alcohol and the amine compound (2) at a high temperature under high pressure; a process of reacting an acid halide compound of the carboxylic acid compound (3), i.e. a carboxylic acid halide, with the amine compound (2), and the like.
The mixed acid anhydride used in the above mixed acid anhydride process (a) is obtained by the know Schotten-Baumann reaction, and the reaction product is used without isolating from the reaction mixture for the reaction with the amine compound (2) to give the desired compound (1) of the present invention. The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. The basic compound is any conventional compounds used for the Schotten-Baumann reaction and includes, for example, organic basic compounds such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]-octane (DABCO), and inorganic basic compounds such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc. The reaction is usually carried out at a temperature from about -20° C. to about 100° C., preferably at 0° C. to about 50° C., for about 5 minutes to about 10 hours, preferably for 5 minutes to about 2 hours.
The reaction between the mixed acid anhydride thus obtained and the amine compound (2) is usually carried out at -20° C. to about 150° C., preferably at 10° C. to about 50° C., for 5 minutes to about 10 hours, preferably for 5 minutes to 5 hours. The mixed acid anhydride process is usually carried out in a solvent. The solvent may be any conventional solvents which are usually used in the mixed acid anhydride process and includes, for example, halogenated hydrocarbons (e.g. chloroform, dichloromethane, dichloroethane, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, etc.), esters (e.g. methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoric triamide, etc.), or a mixture of these solvents. The alkyl halocarbonate ester used in the mixed acid anhydride process includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. In said process, the carboxylic acid compound (3), the alkyl halocarbonate ester and the amine compound (2) are usually used in each equimolar amount, but preferably, the alkyl halocarbonate ester and the carboxylic acid compound (3) are used each in an amount of about 1 to 1.5 mole to 1 mole of the amine compound (2).
Among the above other processes (d), in case of the process of reacting the carboxylic acid halide with the amine compound (2), the reaction is usually carried out in the presence of a basic compound in an appropriate solvent. The basic compound is any conventional compounds and includes, for example, in addition to the basic compounds used for Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, and the like. The solvent includes, for example, in addition to the solvents used in the mixed acid anhydride process, alcohols (e.g. methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve, methylcellosolve, etc.), pyridine, acetone, water, and the like. The amount of the amine compound (2) and the carboxylic acid halide is not critical, but the carboxylic acid halide is usually used at least in equimolar amount, preferably about 1 to 5 moles to 1 mole of the amine compound (2). The reaction is usually carried out at a temperature from about -20° C. to about 180° C., preferably at 0° C. to about 150° C., for about 5 minutes to about 30 hours.
The amido bond producing reaction in Reaction Scheme-1 may also be carried out by reacting the carboxylic acid compound (3) and the amine compound (2) in the presence of a condensing agent such as phosphorus compounds (e.g. triphenylphosphine, diphenylphosphonyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoric azide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, etc. The reaction is usually carried out in the presence of the solvent and the basic compound as used in the above reaction of the carboxylic acid halide and the amide compound (2) at a temperature from -20° C. to 150° C., preferably from 0° C. to about 100° C., for about 5 minutes to about 30 hours. The condensing agent and the carboxylic acid compound (3) are used at least in equimolar amount, preferably about 1 to 2 moles, to 1 mole of the amine compound (2). ##STR6## wherein RA, R1, R2, R3, A, B1 and B2 are the same as defined above.
The reaction of the compound (4) and the compound (5) is carried out in the same conditions as in the reaction of the compound (2) and the compound (3) in Reaction Scheme-1. ##STR7## wherein R, R1, R3, R4, R5, D, I, B1, A and B2 are the same as defined above, R2a is oxo group, R2b is hydroxy group, R2c is a group of the formula: --O--D(CO)I NR4 R5 (D, I, R4 and R5 are the same as defined above), R2d is a lower alkylidene group, R2m is a lower alkoxy group or a lower alkenyloxy group, R21 is a lower alkyl group or a lower alkenyl group, and X is a halogen atom.
The reaction of converting the compound (1a) into the compound (1b) is carried out by subjecting the compound (1a) to reduction reaction. The reduction reaction is preferably carried out by using a hydrogenation agent. The hydrogenation agent includes, for example, lithium aluminum hydride, sodium borohydride, sodium trimethoxyborohydride, lithium borohydride, diborane, and the like. The hydrogenation agent is used at least in an equimolar amount, preferably 1 mole to 15 moles, to 1 mole of the starting compound. The reduction reaction is usually carried out in an appropriate solvent such as water, lower alcohols (e.g. methanol, ethanol, isopropanol, t-butanol, etc.), ethers (e.g. tetrahydrofuran, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, diglyme, etc.), or a mixture thereof, at a temperature from -60° C. to 150° C., preferably at -30° C. to 100° C., for about 10 minutes to about 15 hours. In case that lithium aluminum hydride or diborane is used as a reducing agent, it is preferable to use an anhydrous solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, and the like.
The reaction between the compound (1b) and the compound (6) is usually carried out in an appropriate inert solvent in the presence or absence of a basic compound. The inert solvent includes, for example, aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride, etc.), lower alcohols (e.g. methanol, ethanol, isopropanol, butanol, t-butanol, etc.), acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, or a mixture thereof. The basic compound includes, for example, metal carbonates and metal hydrogen carbonates (e.g. sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), metal hydroxides (sodium hydroxide, potassium hydroxide, etc.), sodium hydride, potassium, sodium, sodium amide, metal alcoholates (e.g. sodium methylate, sodium ethylate, etc.), organic basic compounds (e.g. pyridine, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]-undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and the like. The amount of the compound (1b) and the compound (6) is not critical, but the compound (6) is used at least in an equimolar molar, preferably in an amount of 1 mole to 10 moles, to 1 mole of the compound (1b). The reaction is usually carried out at a temperature from 0° C. to about 200° C., preferably 0° C. to about 170° C., for about 30 minutes to about 30 hours. An alkali metal halide such as sodium iodide, potassium iodide, etc. may be added to this reaction system.
The reaction of converting the compound (1a) into the compound (1d) is carried out in an appropriate solvent in the presence of a phosphonium salt and a basic compound. The phosphonium salt includes, for example, a phosphorus compound of the following formula.
(R.sup.9).sub.3 P.sup.+ --CH.sub.2 --R.sup.10 X--          (7)
wherein
R9 is phenyl group, R10 is hydrogen atom or a lower alkyl group, and X is the same as defined above. The basic compound includes, for example, inorganic bases such as sodium, potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc., and organic bases such as metal alcoholates (e.g. sodium methylate, sodium ethylate, potassium t-butoxide, etc.), alkyl lithium, aryl lithium or lithium amide (e.g. methyl lithium, n-butyl lithium, phenyl lithium, lithium diisopropylamide, etc.), pyridine, piperidine, quinoline, triethylamine, N,N-dimethylaniline, and the like. The solvent may be any one which does not affect the reaction, and includes, for example, ethers (e.g. diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), aliphatic hydrocarbons (e.g. n-hexane, heptane, cyclohexane, etc.), aprotic polar solvents (e.g. pyridine, N,N-dimethylaniline, N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, etc.), alcohols (e.g. methanol, ethanol, isopropanol, etc.), and the like. The reaction is usually carried out at a temperature from -80° C. to 150° C., preferably at a temperature from -80° to about 120° C., for 0.5 to about 15 hours.
The reaction between the compound (1a) and the compound (21) can be carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6). ##STR8## wherein R, R1, A, B1 and B2 are the same as defined above, and R2e is methylidene group.
The reaction of converting the compound (1e) into the compound (1f) is carried out by reacting with an oxidizing agent in the presence of a co-oxidizing agent in an appropriate solvent. The solvent used in the reaction with an oxidizing agent includes, for example, ethers (e.g. pyridine, dioxane, tetrahydrofuran, diethyl ether, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), esters (e.g. ethyl acetate, etc.), water, alcohols (e.g. methanol, ethanol, isopropanol, t-butanol, etc.), or a mixture of these solvents. The co-oxidizing agent includes, N-oxides of organic amines such as pyridine N-oxide, N-ethyldiisopropylamine N-oxide, N-methylmorpholine N-oxide, trimethylamine N-oxide, triethylamine N-oxide, and the like. The oxidizing agent includes, for example, osmium tetraoxide, and the like. The oxidizing agent is used at least in equimolar amount, preferably in an amount of 1 mole to 5 moles, to 1 mole of the starting compound. The reaction is carried out at a temperature from about -20° C. to about 150° C., preferably at a temperature from room temperature to about 100° C., for 1 to about 10 hours. ##STR9## wherein R, R1, R3, R6, R7, E, B1, A and B2 are the same as defined above, R2f is a lower alkoxycarbonyl-substituted lower alkyl group, and R2g is a carboxy-substituted lower alkyl group.
The hydrolysis of the compound (1g) is carried out in the presence of an acid or a basic compound in an appropriate solvent or without a solvent. The solvent includes, for example, water, alcohols (e.g. methanol, ethanol, isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g. acetic acid, formic acid, etc.), or a mixture of these solvents. The acid includes, for example, mineral acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.) and organic acids (e.g. formic acid, acetic acid, aromatic sulfonic acid, etc.). The basic compound includes, for example, metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), and the like. The reaction is usually carried out at a temperature from room temperature to about 200° C., preferably at a temperature from room temperature to about 150° C., for 10 minutes to about 25 hours.
The esterification of the compound (1h) is carried out by reacting the starting compound with an alcohol (e.g. methanol, ethanol, isopropanol, etc.) in the presence of a mineral acid (e.g. hydrochloric acid, sulfuric acid, etc.), or a halogenating agent (e.g. thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride) at a temperature from 0° C. to 150° C., preferably at a temperature from 50° C. to 100° C., for about 1 to about 10 hours.
The reaction between the compound (1h) and the compound (8) is carried out under the same conditions as those of the reaction between the compound (2) and the compound (3) in Reaction Scheme-1. ##STR10## wherein R, R1, R3, A, B1, B2, R4, R5 and D are the same as defined above, R2h is a lower alkoxycarbonyl-substituted lower alkoxy group, R2i is a carboxy-substituted lower alkoxy group.
The hydrolysis of the compound (1j) is carried out under the same conditions as those of the hydrolysis of the compound (1g) in Reaction Scheme-5.
The esterification of the compound (1k) is carried out under the same conditions as those of the esterification of the compound (1h) in Reaction Scheme-5.
The reaction between the compound (1k) and the compound (9) is carried out under the same conditions as those of the reaction between the compound (2) and the compound (3) in Reaction Scheme-1. ##STR11## wherein R, R1, R3, R2h, R4, R5, A, B1, B2, D and X are the same as defined above, R2j is a hydroxy-substituted lower alkoxy group, R11 is a lower alkyl group, R2k is a lower alkylsulfonyloxy-substituted lower alkoxy group, R2l is a phthalimide-substituted lower alkoxy group, M is an alkali metal such as potassium, sodium, etc., R2t is a group of the formula: --O--D--NR4 R5 (wherein D, R4 and R5 are the same as defined above), and R2u is an imidazolyl-substituted lower alkoxy group.
The reaction of converting the compound (1m) into the compound (1n) ia carried out under the same conditions as those of the reaction of converting the compound (1a) into the compound (1b) in Reaction Scheme-3.
The reaction between the compound (1n) and the compound (10) is carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6) in Reaction Scheme-3.
The reaction between the compound (1o) and the compound (11) is carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6) in Reaction Scheme-3.
The reaction of converting the compound (1p) into the compound (1q) is carried out by reacting the compound (1p) with hydrazine, or by hydrolysis of the compound (1p), in an appropriate solvent. The solvent used in the reaction with hydrazine includes, for example, the solvents used for the reaction between the compound (2) and the compound (3) in Reaction Scheme-1 as well as water. The reaction is usually carried out at a temperature from 0° C. to about 120° C., preferably from 0° C. to about 100° C., for 0.5 to about 5 hours. Hydrazine is used at least in equimolar amount, preferably in an amount of 1 mole to 5 moles, to 1 mole of the compound (1p).
The above hydrolysis is carried out in the presence of an acid or a basic compound in an appropriate solvent or without a solvent. The solvent includes, for example, water, alcohols (e.g. methanol, ethanol, isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g. acetic acid, formic acid, etc.), or a mixture of these solvents. The acid includes, for example, mineral acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), and organic acids (e.g. formic acid, acetic acid, aromatic sulfonic acid, etc.). The basic compound includes, for example, metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), and the like. The reaction is usually carried out at a temperature from room temperature to about 200° C., preferably at a temperature from room temperature to about 150° C., for 10 minutes to about 25 hours.
The reaction between the compound (1o) and the compound (27), and the reaction between the compound (1o) and the compound (23) can be carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6) in Reaction Scheme-3. ##STR12## wherein R, R1, R3, A, B1, B2 and X are the same as defined above, R4a is a lower alkyl group, a cycloalkyl group or an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent, R13 and R14 are each hydrogen atom or a lower alkyl group, R4b is a lower alkanoyl group, and R5a is hydrogen atom, a lower alkyl group, a lower alkanoyl group, a cycloalkyl group or an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent.
The reaction between the compound (1r) and the compound (12) is carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6) in Reaction Scheme-3.
The reaction between the compound (1r) and the compound (13) is carried out in the presence of a reducing agent in an appropriate solvent or without a solvent. The solvent includes, for example, water, alcohols (e.g. methanol, ethanol, isopropanol, etc.), acetonitrile, formic acid, acetic acid, ethers (e.g. dioxane, diethyl ether, diglyme, tetrahydrofuran, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), or a mixture thereof. The reducing agent includes, for example, formic acid, alkali metal salts of fatty acids (e.g. sodium formate, etc.), hydrogenation agents (e.g. sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, etc.), catalytic reducing agents (e.g. palladium-black, palladium-carbon, platinum oxide, platinum black, Ranney nickel, etc.), and the like.
When formic acid is used as a reducing agent, the reaction is usually carried out at a temperature from room temperature to about 200° C., preferably at about 50° C. to about 150° C., for about one to about 10 hours. Formic acid is used in an excess amount to the compound (1r).
When a hydrogenation agent is used, the reaction is usually carried out at a temperature from about -30° C. to about 100° C., preferably about 0° C. to about 70° C., for about 30 minutes to about 12 hours. The hydrogenation agent is used in an amount of 1 mole to 20 moles, preferably in an amount of 1 mole to 6 moles, to 1 mole of the compound (1r). Especially, when lithium aluminum hydride is used as a reducing agent, the solvent is preferably ethers (e.g. diethyl ether, dioxane, tetrahydrofuran, diglyme, etc.) or aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.).
Moreover, when a reducing agent is used, the reaction is usually carried out under atmospheric pressure to 20 atms of hydrogen, preferably, under atmospheric pressure to 10 atms of hydrogen, or in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, hydrazine hydrate, etc., at -30° C. to 100° C., preferably at 0° C. to 60° C., for about one to 12 hours. The reducing agent is usually used in an amount of 0.1 to 40% by weight, preferably 1 to 20% by weight to the amount of the compound (1r). The compound (13) is usually used at least in equimolar amount, preferably in equimolar to excess amount, to the compound (1r).
The reaction between the compound (1r) and the compound (14) is carried out under the same conditions as those of the reaction between the compound (2) and the compound (3) in Reaction Scheme-1. ##STR13## wherein R, R1, R3, A, B1, B2, R13, R14, E, R4b, I and X are the same as defined above, R6a is a lower alkyl group or an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent, and R7a is hydrogen atom, a lower alkyl group, an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent, or a lower alkanoyl group.
The reaction between the compound (1u) and the compound (25) is carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6) in Reaction Scheme-3.
The reaction between the compound (1u) and the compound (13) is carried out under the same conditions as those of the reaction between the compound (1r) and the compound (13) in Reaction Scheme-8. The reaction between the compound (1u) and the compound (14) is carried out under the same conditions as those of the reaction between the compound (2) and the compound (3) in Reaction Scheme-1. ##STR14## wherein R, R1, R2, R3, B1, B2, A, R8 and X are the same as defined above.
The reaction between the compound (1wa) or the compound (1wb) and the compound (15) is carried out under the same conditions as those of the reaction between the compound (1b) and the compound (6) in Reaction Scheme-3. ##STR15## wherein R, R1, R2a, R3, A, B1 and B2 are the same as defined above, and R15 and R16 are the same or different and are hydrogen atom, a lower alkyl group or a cycloalkyl group.
The reaction of converting the compound (1a) into the compound (1y) is carried out in the presence or absence of a dehydrating agent in an appropriate solvent or without a solvent. The solvent includes, for example, alcohols (e.g. methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), aprotic polar solvents (e.g. dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc.), or a mixture of these solvents. The dehydrating agent includes, for example, drying agents which are conventionally used for drying solvents (e.g. molecular sieve, etc.), mineral acids (e.g. hydrochloric acid, sulfuric acid, boron trifluoride, etc.), organic acids (e.g. p-toluenesulfonic acid, etc.), or a mixture thereof. The reaction is usually carried out at a temperature from room temperature to 250° C., preferably at a temperature from about 50° C. to about 200° C., for one to about 48 hours. The amount of the compound (16) is not critical, but it is used at least in equimolar amount, preferably 1 mole to excess amount, to 1 mole of the compound (1a). The dehydrating agent is used in an excess amount when a drying agent is used, and when an acid is used as a dehydrating agent, it is used in a catalytic amount.
The subsequent reduction is carried out by various reduction reactions, for example, by catalytic hydrogenation in the presence of a catalyst in an appropriate solvent. The solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane, cyclohexane, etc.), ethers (e.g. diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, diethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g. dimethylformamide, etc.), or a mixture of these solvents. The catalyst is, for example, palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Ranney nickel, and the like. The catalyst is usually used in an amount of 0.02 to 1 mole to 1 mole of the starting compound. The reaction is usually carried out at a temperature from -20° C. to about 100° C., preferably at a temperature from 0° C. to about 70° C., under a pressure of 1 atm to 10 atms of hydrogen, for 0.5 to 20 hours.
The above mentioned conditions for reduction can be employed in the present reduction, but the reduction using a hydrogenation agent is more preferable. The hydrogenation agent includes, for example, lithium aluminum hydride, sodium borohydride, diboran, etc., and is used at least in equimolar amount, preferably in an amount of 1 mole to 10 moles, to 1 mole of the compound (1a). The reduction is carried out in an appropriate solvent such as water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ethers (e.g. tetrahydrofuran, diethyl ether, diglyme, etc.), dimethylformamide, or a mixture of these solvents, at a temperature of about -60° C. to about 50° C., preferably at a temperature from -30° C. to room temperature, for about 10 minutes to about 15 hours. When lithium aluminum hydride or diboran is used as a reducing agent, anhydrous solvent such as diethyl ether, tetrahydrofuran, diglyme, etc., is preferably used.
When at least one of R15 and R16 in the compound (1y) is hydrogen atom, the compound is converted into the compound (1y) wherein at least one of R15 and R16 is a lower alkyl group by reacting it with the compound (12) or the compound (13) under the same conditions as those of the reaction between the compound (1r) and the compound (12) or the compound (13) in Reaction Scheme-8.
The starting compound (3) or (4) can be prepared by the following processes. ##STR16## wherein R17 is a lower alkyl group, and RA and A are the same as defined above.
The reaction between the compound (17) and the compound (18) is carried out under the same conditions as those of the reaction between the compound (2) and the compound (3) in Reaction Scheme-1.
The hydrolysis of the compound (19) is carried out under the same conditions as those of the hydrolysis of the compound (1g) in Reaction Scheme-5. ##STR17## wherein R1, R2, R3, A, B1 and B2 are the same as defined above.
The reaction between the compound (2) and the compound (19) is carried out under the same conditions as those of the reaction between the compound (2) and the compound (3) in Reaction Scheme-1.
The reduction of the compound (20) is carried out, for example, (i) by using a reducing catalyst in an appropriate solvent, or (ii) by using a mixture of a metal or a metal salt and an acid, or a mixture of a metal or a metal salt and an alkali metal hydroxide, sulfide, ammonium salt, etc., as a reducing agent in an inert solvent.
When the method (i) is employed, the solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane, cyclohexane, etc.), ethers (e.g. dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, etc.), or a mixture of these solvents. The reducing catalyst includes, for example, palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Ranney nickel, and the like. The catalyst is usually used in an amount of 0.02 to 1 mole to 1 mole of the starting compound. The reaction is usually carried out at a temperature from about -20° C. to about 150° C., preferably at a temperature from 0° C. to 100° C., under a pressure of 1 atm to 10 atms of hydrogen, for 0.5 to about 10 hours. An acid (e.g. hydrochloric acid) may be added to the reaction system.
When the method (ii) is employed, there is used as a reducing agent a mixture of iron, zinc, tin or stannous chloride and a mineral acid (e.g. hydrochloric acid, sulfuric acid, etc.), or a mixture of iron, iron sulfide, zinc or tin and an alkali metal hydroxide (e.g. sodium hydroxide, etc.), sulfide (e.g. ammonium sulfide, etc.), aqueous ammonia, ammonium salt (e.g. ammonium chloride, etc.). The inert solvent includes, for example, water, methanol, ethanol, dioxane, acetic acid, and the like. The conditions for reduction can be selected according to the kinds of the reducing agent to be used. For example, when a mixture of iron and hydrochloric acid is used as a reducing agent, the reaction is preferably carried out at a temperature from 0° C. to about 100° C., for 0.5 to about 10 hours. The reducing agent may be used at least in equimolar amount, usually in an amount of 1 mole to 20 moles to 1 mole of the starting compound. ##STR18## wherein R1, R2, R3, R18, B1 and B2 are the same as defined above, p is 0, 1 or 2, R18a is a lower alkoxycarbonyl group, and R18b is carboxy group.
The hydrolysis of the compound (1B) is carried out under the same conditions as those of the hydrolysis of the compound (1g) in Reaction Scheme-5. The esterification of the compound (1C) is carried out under the same conditions as those of the esterification of the compound (1h) in Reaction Scheme-5. ##STR19## wherein R1, R2, R3, R18, R19, R20, p, B1 and B2 are the same as defined above, R18c is a lower alkoxycarbonyl-substituted lower alkoxy group, R18d is a carboxy-substituted lower alkoxy group, R18e is a hydroxy-substituted lower alkoxy group, and R18f is a group of the formula: --O--E--CO--NR19 R20 (E, R19 and R20 are the same as defined above).
The hydrolysis of the compound (1D) is carried out under the same conditions as those of the hydrolysis of the compound (1g) in Reaction Scheme-5. The esterification of the compound (1E) is carried out under the same conditions as those of the esterification of the compound (1h) in Reaction Scheme-5.
The reaction of the compound (1E) with the compound (22) is carried out under the same conditions as those of the reaction between the compound (2) and the compound (3) in Reaction Scheme-1.
The reaction of converting the compound (1D) into the compound (1F) is carried out under the same conditions as those of the reaction of converting the compound (1a) into the compound (1b) in Reaction Scheme-3. ##STR20## wherein R1, R2, R18, p, R18e, R11, X, E, R12, R19, R20 and M are the same as defined above.
The reaction of the compound (1F) with the compound (10) is carried out under the same conditions as those of the reaction between the compound (1n) and the compound (10) in Reaction Scheme-7.
The reaction of the compound (1H) with the compound (22) is carried out under the same conditions as those of the reaction between the compound (1n) and the compound (10) in Reaction Scheme-7.
The reaction of the compound (1H) with the compound (11) is carried out under the same conditions as those of the reaction of the compound (1o) with the compound (11) in Reaction Scheme-7.
The reaction of converting the compound (1J) into the compound (1K) is carried out under the same conditions as those of the reaction of converting the compound (1p) into the compound (1q) in Reaction Scheme-7.
In this reaction, there may optionally be obtained a compound of the formula: ##STR21## but which can easily be removed from the desired compounds. ##STR22## wherein R1, R2, R3, R18, X, p, E, R4a, R13 and R14 are the same as defined above, and R19a is hydrogen atom or a lower alkyl group.
The reaction of the compound (1L) with the compound (12) is carried out under the same conditions as those of the reaction between the compound (1r) and the compound (12) in Reaction Scheme-8. The reaction of the compound (1L) with the compound (13) is carried out under the same conditions as those of the reaction between the compound (1r) and the compound (13) in Reaction Scheme-8. ##STR23## wherein R, R1, R2f, B1, B2, R3, R11, X, R12, M, R6 and R7 are the same as defined above, R2m is a hydroxy-substituted lower alkyl group, R2n is a lower alkylsuflonyloxy-substituted lower alkyl group, R2o is a group of the formula: --E--NR6 R7 (E, R6 and R7 are the same as defined above), R2 P is a phthalimide-substituted lower alkyl group, R2q is an imidazolyl-substituted lower alkyl group, R2r is a 1,2,4-triazolyl-substituted lower alkyl group, and R2s is a lower alkanoyloxy-substituted lower alkyl group.
The reaction of converting the compound (1N) into the compound (1O) is carried out under the same conditions as those of the reaction of converting the compound (1m) into the compound (1n) in Reaction Scheme-7. The reaction between the compound (1P) and the compound (8), the reaction of the compound (1P) with the compound (23) and the reaction of the compound (1P) with the compound (24) are carried out under the same conditions as those of the reaction of the compound (1n) with the compound (10) in Reaction Scheme-7.
The reaction of the compound (1P) with the compound (11) is carried out under the same conditions as those of the reaction of the compound (1o) with the compound (11) in Reaction Scheme-7.
The reaction of converting the compound (1R) into the compound (1S) is carried out under the same conditions as those of the reaction of converting the compound (1p) into the compound (1s) in Reaction Scheme-7.
The reaction of converting the compound (1O) into the compound (1V) is carried out by lower-alkanoylating the compound (1O) by using a compound of the formulae: (R22)2 O (26) or R22 X (27) [wherein R22 is a lower alkanoyl group, and X are the same as defined above]. This lower-alkanoylating reaction is carried out in the presence or absence of a basic compound. The basic compound includes, for example, alkali metals (e.g. sodium, potassium, etc.), hydroxides, carbonates, hydrogen carbonates of these alkali metals, or organic bases such as N,N-dimethylaminopyridine, pyridine, piperidine, and the like. The reaction can proceed either without a solvent, or in a solvent. The solvent includes, for example, ketones (e.g. acetone, methyl ethyle ketone, etc.), ethers (e.g. diethyl ether, dioxane, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), water, pyridine, and the like. The compounds (7) and (8) are used at least in equimolar amount to the starting compound, but they are preferably used in an amount of 1 mole to excess amount to 1 mole of the starting compound. The above reaction is carried out at a temperature from 0° to 200° C., preferably at about 0° C. to about 150° C., for 5 minutes to about 5 days.
Among the desired compounds (1) of the present invention, the compound (1) wherein the groups of R6 and R7 form a piperazine ring being substituted by a lower alkoxycarbonyl group at 4-position, can be hydrolyzed under the same conditions as those of the hydrolysis of the compound (1g) in Reaction Scheme-5, and converted into the compound (1) wherein the substituent at 4-position of said piperazine ring is hydrogen atom.
Among the compounds (1), the compound (1) wherein both R2 and R3 are a lower alkoxy group, and they bond at the same position, can be hydrolyzed under the same conditions as those of the hydrolysis of the compound (1g) in Reaction Scheme-5, and converted into the compound (1) wherein R2 is oxo group.
Among the desired compounds (1) of the present invention, the compounds having an acidic group can easily be converted into salts by treating with a pharmaceutically acceptable basic compound. The basic compound includes, for example, metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, etc.), alkali metal carbonates or hydrogen carbonates (e.g. sodium carbonate, sodium hydrogen carbonate, etc.) and alkali metal alcoholates (e.g. sodium methylate, potassium ethylate, etc.). Besides, among the desired compounds (1) of the present invention, the compounds having a basic group can easily be converted into acid addition salts thereof by treating with a pharmaceutically acceptable acid. The acid includes, for example, inorganic acids (e.g. sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, etc.), and organic acids (e.g. acetic acid, p-tolunesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, benzoic acid, etc.). These salts show as well excellent vasopressin antagonistic activity as the desired compounds (1).
In addition, the compounds (1) of the present invention include stereoisomers and optical isomers, and these isomers are also useful as vasopressin antagonist.
The compounds of the present invention thus obtained can easily be isolated and purified by conventional isolation methods. The isolation methods are, for example, distillation method, recrystallization method, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography, extraction with a solvent, and the like.
The desired compounds (1) of the present invention and salts thereof are useful as a vasopressin antagonist, and are used in the form of a conventional pharmaceutical preparation. The preparation is prepared by using conventional diluents or carriers such as fillers, thickening agents, binders, wetting agent, disintegrators, surfactants, lubricants, and the like. The pharmaceutical preparations can be selected from various forms in accordance with the desired utilities, and the representative forms are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), and the like. In order to form in tablets, there are used carriers such as vehicles (e.g. lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.), binders (e.g. water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrators (e.g. dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, starches, lactose, etc.), disintegration inhibitors (e.g. white sugar, stearin, cacao butter, hydrogenated oils, etc.), absorption promoters (e.g. quaternary ammonium base, sodium laurylsulfate, etc.), wetting agents (e.g. glycerin, starches, etc.), adsorbents (e.g. starches, lactose, kaolin, bentonite, colloidal silicates, etc.), lubricants (e.g. purified talc, stearates, boric acid powder, polyethylene glycol, etc.), and the like. Moreover, the tablets may also be in the form of a conventional coated tablet, such as sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film coating tablets, or double or multiple layer tablets. In the preparation of pills, the carriers include vehicles (e.g. glucose, lactose, starches, cacao butter, hydrogenated vegetable oils, kaolin, talc, etc.), binders (e.g. gum arabic powder, tragacanth powder, gelatin, ethanol, etc.), disintegrators (e.g. laminaran, agar, etc.), and the like. In the preparation of suppositories, the carriers include, for example, polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides, and the like. Capsules can be prepared by charging a mixture of the compound of the present invention and the above carriers into hard gelatin capsules or soft capsules in usual manner. In the preparation of injections, the solutions, emulsions and suspensions are sterilized and are preferably made isotonic with the blood. In the preparation of these solutions, emulsions and suspensions, there are used conventional diluents, such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the pharmaceutical preparations may also be incorporated with sodium chloride, glucose, or glycerin in an amount sufficient to make them isotonic, and may also be incorporated with conventional solubilizers, buffers, anesthetizing agents. Besides, the pharmaceutical preparations may optionally be incorporated with coloring agent, preservatives, perfumes, flavors, sweeting agents, and other medicaments, if required.
The amount of the desired compound of the present invention to be incorporated into the vasopressin antagonist is not specified but may be selected from a broad range, but usually, it is preferably in the range of 1 to 70 by weight, more preferably 5 to 50% by weight.
The vasopressin antagonist containing as an active ingredient the compounds (1) of the present invention and a salt thereof may be administered in any method, and suitable method for administration may be determined in accordance with various forms of preparations, ages, sexes and other conditions of the patients, the degree of severity of diseases, and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. The injections are intravenously administered alone or together with a conventional auxiliary liquid (e.g. glucose, amino acid solutions), and further are optionally administered alone in intramuscular, intracutaneous, subcutaneous, or intraperitoneal route, if required. Suppositories are administered in intrarectal route.
The dosage of the vasopressin antagonist of the present invention may be selected in accordance with the usage, ages, sexes and other conditions of the patients, the degree of severity of the diseases, and the like, but it is usually in the range of about 0.6 to 50 mg of the active compound of the present invention per 1 kg of body weight of the patient per day. The active compound is preferably contained in an amount of about 10 to about 1000 mg per the dosage unit.
BEST MODE FOR CARRYING OUT THE INVENTION Examples
The present invention is illustrated in more detail by the following Preparations of vasopressin antagonist, Reference Examples of processes for preparing the starting compounds to be used for preparing the desired compounds of the present invention, and Examples of processes for preparing the desired compounds, and Experiments of the activities of the desired compounds of the present invention.
PREPARATION 1
Film coated tablets are prepared from the following compounds.
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Components                Amount                                          
______________________________________                                    
5-Hydroxy-7-chloro-1-[6-(2-methylbenzoyl-                                 
                          150     g                                       
amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-                                  
benzazepine                                                               
Avicel (trade name of microcrystalline cellulose                          
                          40      g                                       
manufactured by Asahi Chemical Industry, Co.,                             
Ltd. Japan)                                                               
Corn starch               30      g                                       
Magnesium stearate        2       g                                       
Hydroxypropyl methylcellulose                                             
                          10      g                                       
Polyethylene glycol-6000  3       g                                       
Castor oil                40      g                                       
Ethanol                   40      g                                       
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The active compound of the present invention, Avicel, corn starch and magnesium stearate are mixed and kneaded and the mixture is tabletted using a conventional pounder (R 10 mm) for sugar coating. The tablets thus obtained are coated with a film coating agent consisting of hydroxypropyl methylcellulose, polyethylene glycol-6000, castor oil and ethanol to give film coated tablets.
PREPARATION 2
Tablets are prepared from the following components.
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Components                 Amount                                         
______________________________________                                    
5-Hydroxy-7-chloro-1-[2-(5-methylbenzoylamino)-                           
                           150    g                                       
thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine                                
Citric acid                1.0    g                                       
Lactose                    33.5   g                                       
Dicalcium phosphate        70.0   g                                       
Pullonic F-68              30.0   g                                       
Sodium laurylsulfate       15.0   g                                       
Polyvinylpyrrolidone       15.0   g                                       
Polyethylene glycol (Carbowax 1500)                                       
                           4.5    g                                       
Polyethylene glycol (Carbowax 6000)                                       
                           45.0   g                                       
Corn starch                30.0   g                                       
Dry sodium stearate        3.0    g                                       
Dry magnesium stearate     3.0    g                                       
Ethanol                    q.s.                                           
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The active compound of the present invention, citric acid, lactose, dicalcium phosphate, Pullonic F-68 and sodium laurylsulfate are mixed. The mixture is screened with No. 60 screen and is granulated with an alcohol solution containing polyvinylpyrrolidone, Carbowax 1500 and 6000. If required, an alcohol is added thereto so that the powder mixture is made a paste-like mass. Corn starch is added to the mixture and the mixture is continuously mixed to form uniform particles. The resulting particles are passed through No. 10 screen and entered into a tray and then dried in an oven at 100° C. for 12 to 14 hours. The dried particles are screened with No. 16 screen and thereto are added dry sodium laurylsulfate and dry magnesium stearate, and the mixture is tabletted to form the desired shape.
The core tablets thus prepared are vanished and dusted with talc in order to guard from wetting. Undercoating is applied to the core tablets. In order to administer the tablets orally, the core tablets are vanished several times. In order to give round shape and smooth surface to the tablets, further undercoating and coating with lubricant are applied thereto. The tablets are further coated with a coloring coating material until the desired colored tablets are obtained. After drying, the coated tablets are polished to obtain the desired tablets having uniform gloss.
PREPARATION 3
An injection preparation is prepared from the following components.
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Components                 Amount                                         
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5-Hydroxy-7-chloro-1-[2-(2-methylbenzoyl-                                 
                           5      g                                       
amino)-5-thiazolylcarbonyl]-2,3,4,5-tetrahydro-                           
1H-benzazepine                                                            
Polyethylene glycol (molecular weight: 4000)                              
                           0.3    g                                       
Sodium chloride            0.9    g                                       
Polyoxyethylene sorbitan monooleate                                       
                           0.4    g                                       
Sodium metabisulfite       0.1    g                                       
Methyl-paraben             0.18   g                                       
Propyl-paraben             0.02   g                                       
Distilled water for injection                                             
                           10.0   ml                                      
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The above parabens, sodium metabisulfite and sodium chloride are dissolved with stirring in distilled water of half volume of the above with stirring at 80° C. The solution thus obtained is cooled to 40° C., and the active compound of the present invention and further polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution. To the solution is added distilled water for injection to adjust to the desired volume, and the solution is sterilized by filtering with an appropriate filter paper to give an injection preparation.
REFERENCE EXAMPLE 1
To 6-nitronicotinic acid (3.5 g) is added thionyl chloride (50 ml), and the mixture is refluxed for three hours, and evaporated to remove thionyl chloride to give 6-nitronicotinoyl chloride, which is added with stirring to a solution of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzazepine (3.4 g) in pyridine (50 ml) under ice-cooling. The mixture is stirred at room temperature overnight. To the reaction mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed successively with 0.1N aqueous hydrochloric acid and water, and dried over magnesium sulfate. The resultant is evaporated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography to give 7-chloro-5-oxo-1-(6-nitronicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine (4.9 g) as colorless amorphous.
1 H-NMR (CDCl3)δ:1.85-2.60 (2H, m), 2.75-2.95 (2H, m), 3.10-4.00 (1H, m), 4.20-5.20 (1H, m), 6.55-6.75 (1H, m), 7.15-7.30 (1H, m), 7.75-7.90 (2H, m), 8.12 (1 H, d, J=8.3 Hz), 8.46 (1 H, s).
REFERENCE EXAMPLE 2
2N Hydrochloric acid (50 ml) is added to reduced iron (23.5 g), and the mixture is allowed to stand for 10 minutes. The mixture is filtered, and washed with water and acetone, and then, dried. To 7-chloro-5-oxo-1-(6-nitronicotinoyl)-2,3,4,5-1H-tetrahydro-benzazepine (9.4 g) is added acetic acid (100 ml), and thereto is added gradually the above reduced iron at 80° C. The mixture is stirred at the same temperature for 30 minutes, and filtered on Celite. The filtrate is neutralized with sodium hydrogen carbonate, and extracted with dichloromethane. The extract is washed with water, and dried over magnesium sulfate. The resultant is evaporated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography, and further recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-oxo-1-(6-aminonicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine (6.5 g) as white powder.
M.p. 210°-213° C.
REFERENCE EXAMPLE 3
Using the suitable starting compounds, the following compounds are obtained in the same manner as in Reference Example 1.
7-Chloro-5-methoxycarbonylmethyl-1-(6-nitronicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine
White powder
M.p. 162°-165° C. (recrystallized from dichloromethane-diethyl ether).
7-Chloro-5-methoxycarbonylmethoxy-1-(6-nitronicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine
White powder
M.p. 154°-157° C. (recrystallized from dichloromethane-diethyl ether).
7-Chloro-1-(6-nitronicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine
White powder
M.p. 171°-174° C. (recrystallized from dichloromethane-diethyl ether).
7-Chloro-4-methyl-1-(6-nitronicotinoyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
Colorless amorphous
1 H-NMR (CDCl3)δ:2.44 (3H, s), 3.00-3.30 (3H, m), 3.73 (1H, d, J=14.1 Hz), 4.02 (1H, d, J=14.1 Hz), 4.80-4.95 (1H, m), 6.56 (1 H, d, J=8.3 Hz), 7.00 (1 H, dd, J=2.4, 8.3 Hz), 7.15-7.60 (1 H, m), 7.92 (1 H, dd, J=2.1, 8.3 Hz), 8.14 (1H, d, J=8.2 Hz), 8.36 (1H, d, J=1.7 Hz).
7-Chloro-5-oxo-1-(5-nitrothenoyl)-2,3,4,5-tetrahydro-1H-benzazepine
White powder
M.p. 166°-169° C. (recrystallized from dichloromethane-diethyl ether).
7-Chloro-5-oxo-1-(5-nitro-2-furoyl)-2,3,4,5-tetrahydro-1H-benzazepine
White powder
M.p. 124°-126° C. (recrystallized from dichloromethane-diethyl ether).
7-Chloro-5-oxo-1-(5-nitro-2-thiazolyl)-2,3,4,5-tetrahydro-1H-benzazepine
White powder
M.p. 149°-152° C. (recrystallized from dichloromethane-diethyl ether).
7-Chloro-5-oxo-1-(5-nitro-1-pyridylcarbonyl)-2,3,4,5-tetrahydro-1H-benzazepine
Yellow powder
1 H-NMR (CDCl3)δ:1.70-2.75 (2H, m), 2.80-3.70 (3H, m), 4.60-5.30 (1 H, m), 6.59 (1 H, d, J=8.3 Hz), 7.15 (1 H, dd, J=2.4, 8.3 Hz), 7.89 (1H, d, J=2.4 Hz), 7.94 (1 H, d, J=8.6 Hz), 8.52 (1 H, dd, J=2.4, 8.5 Hz), 9.02 (1 H, d, J=2.4 Hz).
7-Chloro-5-methyl-1-(6-nitronicotinoyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
Orange powder
M.p. 162.5°-164° C. (recrystallized from dichloromethane-diethyl ether).
REFERENCE EXAMPLE 4
Using the suitable starting compounds, the following compounds are obtained in the same manner as in Reference Example 2.
7-Chloro-5-methoxycarbonylmethyl-1-(6-aminonicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine
White powder
M.p. 201°-204° C. (recrystallized from dichloromethane-diethyl ether).
7-Chloro-5-methoxycarbonylmethoxy-1-(6-aminonicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine
Colorless amorphous
1 H-NMR (CDCl3)δ:1.60-2.60 (4H, m), 2.60-3.00 (1H, m), 3.77 (3H, s), 4.05-4.45 (2H, m), 4.50-5.20 (2H, m), 4.70 (2H, s), 6.30 (1 H, d, J=8.6 Hz), 6.60-6.75 (1H, m), 7.05 (1H, d, J=2.4, 8.3 Hz), 7.10-7.70 (2H, m), 7.80-8.15 (1H, m).
7-Chloro-1-(6-aminonicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine
White powder
M.p. 228°-231° C. (recrystallized from dichloromethane-diethyl ether).
7-Chloro-4-methyl-1-(6-aminonicotinoyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
Colorless amorphous
1 H-NMR (CDCl3)δ:2.41 (3H, s), 3.00 (3H, s), 3.67 (1 H, d, J=14 Hz), 3.99 (1H, d, J=14 Hz), 4.68 (2H, s), 4.80 -5.10 (1H, m), 6.28 (1 H, d, J=8.6 Hz), 6.66 (1 H, d, J=8.4 Hz), 7.02 (1 H, dd, J=2.4, 8.4 Hz), 7.29 (1 H, d, J=2.3 Hz), 7.32 (1 H, dd, J=2.3, 8.6 Hz), 7.90 (1 H, d, J=2.3 Hz).
7-Chloro-5-oxo-1-(5-aminothenoyl)-2,3,4,5-tetrahydro-1H-benzazepine
Yellow powder
1 H-NMR (CDCl3)δ:2.00-2.25 (2H, m), 2.65-2.85 (2H, m), 3.75-4.70 (4H, m), 5.83 (1H, d, J=4.1 Hz), 6.40 (1H, d, J=4.1 Hz), 7.16 (1H, d, J=8.4 Hz), 7.42 (1 H, dd, J=2.5, 8.4 Hz), 7.87 (1 H, d, J=2.5 Hz).
7-Chloro-5-oxo-1-(5-amino-2-furoyl)-2,3,4,5-tetrahydro-1H-benzazepine
Green powder
M.p. 151°-154° C. (recrystallized from dichloromethane-diethyl ether).
7-Chloro-5-oxo-1-(5-amino-2-thiazolyl)-2,3,4,5-tetrahydro-1H-benzazepine
Yellow powder
M.p. 142°-144.5° C. (recrystallized from dichloromethane-diethyl ether).
7-Chloro-5-oxo-1-(5-amino-2-pyridylcarbonyl)-2,3,4,5-tetrahydro-1H-1,5-benzazepine
Yellow powder
M.p. 143°-144.5° C. (recrystallized from dichloromethane-diethyl ether).
7-Chloro-5-methyl-1-(6-aminonicotinoyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
White powder
M.p. 191°-193° C. (recrystallized from dichloromethane-diethyl ether).
REFERENCE EXAMPLE 5
To a solution of 6-aminonicotinic acid methyl ester (4 g) in pyridine (40 ml) is added with stirring 2-methylbenzoyl chloride (6.73 g) under ice-cooling, and the mixture is stirred at room temperature overnight. To the reaction solution is added water, and the precipitated crystals are collected by filtration, and dried to give 6-(2-methylbenzoylamino)nicotinic acid methyl ester (5.7 g) as white powder.
M.p. 167°-169° C.
REFERENCE EXAMPLE 6
To a solution of 6-(2-methylbenzoylamino)nicotinic acid methyl ester (2.1 g) in methanol (30 ml) is added 5% aqueous sodium hydroxide solution (24 ml), and the mixture is refluxed for two hours. To the reaction solution is added water, and the mixture is made weak acidic with 1N aqueous hydrochloric acid solution, and then, extracted with diethyl ether. The extract is dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent to give 6-(2-methylbenzoylamino)nicotinic acid (2.1 g) as white powder.
M.p. 235°-238° C.
REFERENCE EXAMPLE 7
Using the suitable starting compounds, there are obtained the following compounds in the same manner as in Reference Example 1.
7-Chloro-5-methoxy-1-(6-nitronicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine
Yellow powder
M.p. 173°-175° C. (recrystallized from dichloromethane-diethyl ether).
7-Chloro-5-allyloxy-1-(6-nitronicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine
Yellow powder
M.p. 116°-120° C. (recrystallized from dichloromethane-diethyl ether).
REFERENCE EXAMPLE 8
Using the suitable starting compounds, there are obtained the following compounds in the same manner as in Reference Example 2.
7-Chloro-5-methoxy-1-(6-aminonicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine
Colorless amorphous
1 H-NMR (CDCl3)δ:1.40-2.55 (4H, m), 2.55-3.00 (1 H, m), 3.30-3.60 (3H, m), 4.20-5.20 (2H, m), 4.66 (2H, brs), 6.30 (1H, d, J=8.5 Hz), 6.66 (1H, d, J=8.4 Hz), 7.03 (1H, dd, J=2.4, 8.3 Hz), 7.30-7.65 (2H, m), 7,80-8.10 (1H, m).
7-Chloro-5-allyloxy-1-(6-aminonicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine
Colorless amorphous
1 H-NMR (CDCl3)δ:1.50-2.60 (4H, m), 2.60-3.00 (1 H, m), 4.00-4.30 (2H, m), 4.40-4.80 (4H, m), 5.00-5.50 (2H, m), 5.80-6.20 (1H, m), 6.29 (1H, d, J=8,4 Hz), 6.65 (1H, d, J=8.3 Hz), 7.03 (1H, dd, J=2.3, 8.3 Hz), 7.10-7.70 (2H, m), 7.80-8.10 (1H, m).
EXAMPLE 1
To a solution of 7-chloro-5-oxo-1-(6-aminonicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g) in pyridine (2 ml) is added with stirring 2-methylbenzoyl chloride (0.18 g) under ice-cooling, and the mixture is stirred at room temperature for one hour. To the reaction solution is added water, and the mixture is extracted with ethyl acetate. The extract is washed successively with 0.1N aqueous hydrochloric acid solution and water, and dried over magnesium sulfate. The resultant is evaporated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography to give 7-chloro-5-oxo-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) as colorless amorphous.
1 H-NMR (CDCl3)δ:2.0-2.4 (2H, m), 2.50 (3H, s), 2.89 (2H, t, J=6.2 Hz), 3.2-5.0 (2H, br), 6.72 (1H, d, J=8.4 Hz), 7.20-7.51 (5H, m), 7.60 (1H, dd, J=2.3, 8.7 Hz), 7.86 (1H, d, J=2.5 Hz), 8.09 (1H, d, J=1.7 Hz), 8.24 (1H, d, J=8.7 Hz), 8.50 (1 H, s).
EXAMPLE 2
To a solution of 7-chloro-5-oxo-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) in methanol (5 ml) is added with stirring sodium borohydride (0.05 g) under ice-cooling, and the mixture is stirred at room temperature for one hour. To the reaction solution is added water, and the mixture is extracted with dichloromethane. The extract is washed with water, and dried over magnesium sulfate. The resultant is evaporated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography to give 7-chloro-5-hydroxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.2 g) as colorless amorphous.
1 H-NMR (CDCl3)δ:1.60-2.60 (4H, m), 2.46 (3H, s), 2.70-2.95 (1 H, m), 3.73 (1 H, s), 4.65-5.65 (2H, m), 6.57 (1 H, d, J=8.1 Hz), 7.00 (1 H, d, J=6.5 Hz), 7.15-8.40 (8H, m), 8.70-8.90 (1H, m).
EXAMPLE 3
To a suspension of methyltriphenylphosphonium bromide (0.86 g) in tetrahydrofuran (20 ml) is added with stirring potassium t-butoxide (0.23 g) at -5° C., and the mixture is stirred at -5° C. for one hour. To the mixture is added 7-chloro-5-oxo-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.58 g) at the same temperature, and the mixture is stirred at room temperature for one hour. The reaction mixture is poured into ice-water, and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-methylidene-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.28 g) as yellow amorphous.
1 H-NMR (CDCl3)δ:1.85-2.20 (2H, m), 2.30-3.30 (3H, m), 2.50 (3H, s), 4.75-5.15 (1 H, m), 5.20-5.35 (2H, m), 6.61 (1 H, d, J=8.3 Hz), 7.01 (1 H, dd, J=2.5, 8.4 Hz), 7.20-7.60 (6H, m), 8.06 (1 H, d, J=2 Hz), 8.19 (1 d, J=8.7 Hz), 8.34 (1 H, s).
EXAMPLE 4
To a solution of 7-chloro-5-methylidene-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.28 g) in t-butanol (3 ml), pyridine (0.2 ml) and water (1.2 ml) is added 4% aqueous osmium tetraoxide solution (0.2 ml), and further thereto is added 4-methylmorpholine N-oxide (0.1 g). The mixture is refluxed for 5 hours, and cooled. Saturated aqueous sodium hydrogen sulfite solution is added to the reaction mixture, and the mixture is stirred at room temperature for 30 minutes. Water is added to the reaction solution, and the mixture is extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-hydroxymethyl-5-hydroxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.14 g) as colorless amorphous.
1 H-NMR (CDCl3)δ:1.50-2.60 (3H, m), 2.45 (3H, s), 2.60-2.95 (1H, m), 3.60-4.25 (4H, m), 4.70-5.10 (1H, m), 6.54 (1H, d, J=8.3 Hz), 6.99 (1H, dd, J=2.3, 8.3 Hz), 7.10-7.70 (5H, m), 7.82 (1 H, d, J=2.3 Hz), 8.10-8.30 (2H, m), 8.83 (1H, s).
EXAMPLE 5
To a suspension of 7-chloro-5-methoxycarbonylmethyl-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.6 g) in ethanol (20 ml) is added 5N aqueous sodium hydroxide solution (4 ml), and the mixture is stirred at room temperature for 4 hours. Water is added to the reaction solution, and the mixture is made weak acidic with diluted hydrochloric acid, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is crystallized from diethyl ether, and further recrystallized from diethyl ether to give 7-chloro-5-carboxymethyl-1-[6-(2 -methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.5 g) as white powder.
M.p. 187°-190° C.
EXAMPLE 6
To a solution of 7-chloro-5-carboxymethyl-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.35 g) in dichloromethane (10 ml) is added with stirring N,N-bis(2-oxo-3-oxazolydinyl)phosphinic chloride (0.24 g) under ice-cooling, and the mixture is stirred at room temperature for 15 minutes. To the mixture are added with stirring dimethylamine hydrochloride (0.078 g) and triethylamine (0.31 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed successively with diluted aqueous sodium hydroxide solution and water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-dimethylaminocarbonylmethyl-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.29 g) as white powder.
M.p. 197°-198.5° C.
EXAMPLE 7
To a suspension of 7-chloro-5-methoxycarbonylmethoxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) in ethanol (5 ml) is added 5N aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 4 hours. Water is added to the reaction mixture, and the mixture is made weak acidic by adding thereto diluted hydrochloric acid, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is crystallized from diethyl ether to give 7-chloro-5-carboxymethoxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as white powder.
M.p. 220°-222° C.
EXAMPLE 8
To a solution of 7-chloro-5-carboxymethoxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) in dichloromethane (10 ml) is added with stirring N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.2 g) under ice-cooling, and the mixture is stirred at room temperature for 15 minutes. Subsequently, to the mixture are added with stirring N-methylpiperazine (0.09 ml) and triethylamine (0.17 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethoxy]-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g) as colorless amorphous.
1 H-NMR (CDCl3)δ:1.60-2.60 (8H, m), 2.29, 2.32 (3H, s), 2.50 (3H, s), 2.70-3.05 (1H, m), 3.40-3.80 (4H, m), 4.10-4.50 (2H, m), 4.55-5.20 (2H, m), 6.60-6.75 (1H, m), 7.00-7.15 (1H, m), 7.15-7.85 (6H, m), 8.10-8.40 (3H, m).
EXAMPLE 9
To a solution of 7-chloro-5-methoxycarbonylmethoxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.2 g) in tetrahydrofuran (15 ml) is added with stirring lithium borohydride (0.1 g) under ice-cooling, and the mixture is stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-hydroxyethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.73 g) as colorless amorphous.
1 H-NMR (CDCl3)δ:1.50-2.60 (4H, m), 2.51 (3H, s), 2.70-3.05 (1 H, m), 3.50-4.05 (4H, m), 4.50-5.15 (2H, m), 6.60-6.75 (1H, m), 7.00-7.15 (1H, m), 7.20-7.85 (6H, m), 8.10-8.40 (3H, m).
EXAMPLE 10
To a solution of 7-chloro-5-(2-hydroxyethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in pyridine (5 ml) is added with stirring methanesulfonyl chloride (0.11 ml) under ice-cooling, and the mixture is stirred at room temperature for two hours. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-methanesulfonyloxyethoxyl)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) as colorless amorphous.
1 H-NMR (CDCl3)δ:1.50-2.60 (4H, m), 2.50 (3H, s), 2.70-3.20 (1 H, m), 2.93, 3.13 (3H, s), 3.70-4.05 (2H, m), 4.20-5.20 (4H, m), 6.64 (1H, d, J=8.1 Hz), 7.00-7.10 (1H, m), 7.20-7.85 (6H, m), 8.05-8.40 (3H, m).
EXAMPLE 11
To a solution of 7-chloro-5-(2-methanesulfonyloxyethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) in dimethylformamide (10 ml) is added potassium phthalimide (0.2 g), and the mixture is stirred at 110° C. for one hour. The reaction solution is poured into ice-water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-phthalimidoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) as colorless amorphous.
1 H-NMR (CDCl3)δ:1.45-2.55 (4H, m), 2.51 (3H, s), 2.60-2.95 (1H, m), 3.70-4.20 (2H, m), 4.50-5.15 (2H, m), 6.58 (1H, d, J=8.2 Hz), 6.99 (1d, J=8.5 Hz), 7.20-8.50 (15H, m).
EXAMPLE 12
To a solution of 7-chloro-5-(2-phthalimidoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.26 g) in ethanol (10 ml) is added hydrazine hydrate (0.04 ml), and the mixture is refluxed for 2 hours, and cooled. Water is added to the reaction solution, and the mixture is made acidic with diluted hydrochloric acid, and washed with diethyl ether. Aqueous sodium hydroxide solution is added to the aqueous layer in order to make it basic, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-aminoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.26 g) as colorless amorphous.
1 H-NMR (CDCl3)δ:1.50-2.60 (4H, m), 2.50 (3H, s), 2.65-3.20 (3H, m), 3.40-3.80 (2H, m), 4.45-5.15 (2H, m), 6.62 (1 H, d, J=8.1 Hz), 7.04 (1H, d, J=8.1 Hz), 7.15-7.85 (6H, m), 8.10-8.50 (3H, m).
EXAMPLE 13
To a solution of 7-chloro-5-(2-aminoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.16 g) in methanol (3 ml) are added 37% formaldhyde (0.3 ml) and sodium cyanoborohydride (0.06 g), and further thereto is added with stirring acetic acid (0.25 ml) at 10° C. The mixture is stirred at room temperature for 3 hours, and poured into ice-water. The mixture is made basic with potassium carbonate, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-dimethylaminoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (58 mg) as colorless amorphous.
1 H-NMR (CDCl3)δ:1.50-3.00 (13H, m), 2.50 (3H, s), 3.40-3.85 (2H, m), 4.45-5.15 (2H, m), 6.60 (1H, d, J=8.1 Hz), 7.00-7.10 (1H, m), 7.20- 7.90 (6H, m), 8.05-8.60 (3H, m).
EXAMPLE 14
To a solution of 7-chloro-5-(2-aminoethoxyl)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.14 g) in dichloromethane (5 ml) are added with stirring triethylamine (0.08 ml) and acetyl chloride (0.03 ml) under ice-cooling. The mixture is stirred at room temperature for 30 minutes, and thereto is added water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-acetylaminoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (85 mg) as colorless amorphous.
1 H-NMR (CDCl3)δ:1.60-2.70 (6H, m), 2.50 (3H, s), 2.70-3.00 (1 H, m), 3.00-3.20 (1H, m), 3.40-3.80 (4H, m), 4.50-5.10 (2H, m), 5.95-6.15 (1H, m), 6.65-6.80 (1 H, m), 7.00-7.20 (1 H, m), 7.20-7.80 (6H, m), 8.05-8.50 (3H, m).
EXAMPLE 15
To a suspension of 7-chloro-5-oxo-1-[5-(2-methylbenzoylamino)thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1 g) in methanol (40 ml) are added molecular sieve 4A (2 g) and 40% methylamine methanol solution (10 ml), and the mixture is refluxed for 6 hours, and cooled. To the mixture is added with stirring sodium borohydride (0.13 g) at room temperature, and the mixture is stirred at the same temperature overnight. The reaction solution is filtered on Celite, and to the filtrate is added water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-methylamino-1-[5-(2-methylbenzoylamino)thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.93 g) as white powder.
M.p. 213°-216° C. (recrystallized from dichloromethane-diethyl ether).
EXAMPLE 16
To a solution of 7-chloro-5-methylamino-1-[5-(2-methylbenzoylamino)thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g) in methanol (10 ml) are added 37% formaldehyde (0.8 ml) and sodium cyanoborohydride (0.1 g), and further thereto is added dropwise acetic acid (0.6 ml) at a temperature below 10° C. The mixture is stirred at room temperature for one hour, and poured into ice-water. The mixture is made basic with potassium carbonate, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-dimethylamino-1-[5-(2-methylbenzoylamino)thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.41 g) as colorless amorphous.
1 H-NMR (CDCl3)δ:1.20-2.60 (10H, m), 2.44 (3H, s), 3.15-3.65 (2H, m), 4.00-5.00 (1H, m), 6.50 (2H, s), 6.90-7.50 (6H, m), 7.67 (1 H, s), 8.73 (1H, s).
EXAMPLE 17
To a suspension of 6-(2-methylbenzoylamino)nicotinic acid (0.3 g) in dimethylformamide (0.5 ml) and dichloromethane (2.5 ml) is added dropwise oxazolyl chloride (0.2 ml), and the mixture is stirred at room temperature for 2 hours. The mixture is evaporated under reduced pressure to remove the solvent to give 6-(2-methylbenzoylamino)nicotinoyl chloride.
To a solution of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzazepine (0.15 g) in pyridine (5 ml) is added with stirring the above obtained 6-(2-methylbenzoylamino)nicotinoyl chloride, and the mixture is stirred at room temperature for 4 hours. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-oxo-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro- 1H-benzazepine (0.16 g) as colorless amorphous.
1 H-NMR (CDCl3)δ:2.0-2.4 (2H, m), 2.50 (3H, s), 2.89 (2H, t, J=6.2 Hz), 3.2-5.0 (2H, br), 6.72 (1H, d, J=8.4 Hz), 7.20-7.51 (5H, m), 7.60 (1H, dd, J=2.3, 8.7 Hz), 7.86 (1H, d, J=2.5 Hz), 8.09 (1H, d, J=1.7 Hz), 8.24 (1H, d, J=8.7 Hz), 8.50 (1H, s).
EXAMPLES 18-148
Using the suitable starting compounds, the following compounds listed in Table 1 are obtained in the same manner as in Examples 1 and 17. Table 2 shows the NMR analysis of these compounds.
              TABLE 1                                                     
______________________________________                                    
 ##STR24##                                                                
______________________________________                                    
Example 18                                                                
Structure:                                                                
 ##STR25##                                                                
R.sup.2 : O (5-position)                                                  
R.sup.3 : H                                                               
 ##STR26##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Methanol                                       
Melting point: 172-174.5° C.                                       
Form: Free                                                                
Example 19                                                                
Structure:                                                                
 ##STR27##                                                                
R.sup.2 : O (5-position)                                                  
R.sup.3 : H                                                               
 ##STR28##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 234-237° C.                                         
Form: Free                                                                
Example 20                                                                
Structure:                                                                
 ##STR29##                                                                
R.sup.2 : O (5-position)                                                  
R.sup.3 : H                                                               
 ##STR30##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 194-196° C.                                         
From: Free                                                                
Example 21                                                                
Structure                                                                 
 ##STR31##                                                                
R.sup.2 : O (5-position)                                                  
R.sup.3 : H                                                               
 ##STR32##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Methanol                                       
Melting point: 206-207° C.                                         
From: Free                                                                
Example 22                                                                
 ##STR33##                                                                
R.sup.2 : O (5-position)                                                  
R.sup.3 : H                                                               
 ##STR34##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Methanol                                       
Melting point: 169.5-171.5° C.                                     
From: Free                                                                
Example 23                                                                
Structure:                                                                
 ##STR35##                                                                
R.sup.2 : O (5-position)                                                  
R.sup.3 : H                                                               
 ##STR36##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Methanol                                       
Melting point: 169.5-172.5° C.                                     
Form: Free                                                                
Example 24                                                                
Structure:                                                                
 ##STR37##                                                                
R.sup.2 : O (5-position)                                                  
R.sup.3 : H                                                               
 ##STR38##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Methanol                                       
Melting point: 173-174° C.                                         
Form: Free                                                                
Example 25                                                                
Structure:                                                                
 ##STR39##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR40##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis: 1)                                                          
Form: Free                                                                
Example 26                                                                
Structure:                                                                
 ##STR41##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR42##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis: 2)                                                          
Form: Free                                                                
Example 27                                                                
Structure:                                                                
 ##STR43##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR44##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis: 3)                                                          
Form: Free                                                                
Example 28                                                                
Structure:                                                                
 ##STR45##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR46##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis 4)                                                           
Form: Free                                                                
Example 29                                                                
Structure:                                                                
 ##STR47##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR48##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis: 5)                                                          
Form: Free                                                                
Example 30                                                                
Structure:                                                                
 ##STR49##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR50##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis: 6)                                                          
Form: Free                                                                
Example 31                                                                
Structure:                                                                
 ##STR51##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR52##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis 7)                                                           
Form: Free                                                                
Example 32                                                                
Structure:                                                                
 ##STR53##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR54##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis: 8)                                                          
Form: Free                                                                
Example 33                                                                
Structure:                                                                
 ##STR55##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR56##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis: 9)                                                          
Form: Free                                                                
Example 34                                                                
Structure:                                                                
 ##STR57##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : CH.sub.2 OH (5-position)                                        
 ##STR58##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis 10)                                                          
Form: Free                                                                
Example 35                                                                
Structure:                                                                
 ##STR59##                                                                
 ##STR60##                                                                
R.sup.3 : H                                                               
 ##STR61##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis: 11)                                                         
Form: Free                                                                
Example 36                                                                
Structure:                                                                
 ##STR62##                                                                
R.sup.2 : OCH.sub.2 CH.sub.2 OH (5-position)                              
R.sup.3 : H                                                               
 ##STR63##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis: 12)                                                         
Form: Free                                                                
Example 37                                                                
Structure:                                                                
 ##STR64##                                                                
R.sup.2 : OCH.sub.2 CH.sub.2 N(CH.sub.3 ).sub.2 (5-position)              
R.sup.3 : H                                                               
 ##STR65##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis 13)                                                          
Form: Free                                                                
Example 38                                                                
Structure:                                                                
 ##STR66##                                                                
R.sup.2 : OCH.sub.2 CH.sub.2 NHCOCH.sub.3 (5-position)                    
R.sup.3 : H                                                               
 ##STR67##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis: 14)                                                         
Form: Free                                                                
Example 39                                                                
Structure:                                                                
 ##STR68##                                                                
R.sup.2 : CH.sub.2 COOH (5-position)                                      
R.sup.3 : H                                                               
 ##STR69##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 187-190° C.                                         
Form: Free                                                                
Example 40                                                                
Structure:                                                                
 ##STR70##                                                                
R.sup.2 : CH.sub.2 CONH.sub.2 (5-position)                                
R.sup.3 : H                                                               
 ##STR71##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 141-144° C.                                         
Form: Free                                                                
Example 41                                                                
Structure:                                                                
 ##STR72##                                                                
R.sup.2 : CH.sub.2 CON(CH.sub.3).sub.2 (5-position)                       
R.sup.3 : H                                                               
 ##STR73##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 197-198.5° C.                                       
Form: Free                                                                
Example 42                                                                
Structure:                                                                
 ##STR74##                                                                
 ##STR75##                                                                
R.sup.3 : H                                                               
 ##STR76##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis: 15)                                                         
Form: Free                                                                
Example 43                                                                
Structure:                                                                
 ##STR77##                                                                
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR78##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 194-197° C.                                         
Form: Free                                                                
Example 44                                                                
Structure:                                                                
 ##STR79##                                                                
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR80##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 193-195° C.                                         
Form: Free                                                                
Example 45                                                                
Structure:                                                                
 ##STR81##                                                                
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR82##                                                                
Crystalline form: Yellow powder                                           
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 205.5-208.5° C.                                     
Form: Free                                                                
Example 46                                                                
Structure:                                                                
 ##STR83##                                                                
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR84##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 182-183.5° C.                                       
Form: Free                                                                
Example 47                                                                
Structure:                                                                
 ##STR85##                                                                
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR86##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis: 16)                                                         
Form: Free                                                                
Example 48                                                                
Structure:                                                                
 ##STR87##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR88##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 238.5-240° C.                                       
Form: Free                                                                
Example 49                                                                
Structure:                                                                
 ##STR89##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR90##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 235-237° C.                                         
Form: Free                                                                
Example 50                                                                
Structure:                                                                
 ##STR91##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR92##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 196-199° C.                                         
Form: Free                                                                
Example 51                                                                
Structure:                                                                
 ##STR93##                                                                
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR94##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 180-183° C.                                         
Form: Free                                                                
Example 52                                                                
Structure:                                                                
 ##STR95##                                                                
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR96##                                                                
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 167-169.5° C.                                       
Form: Free                                                                
Example 53                                                                
Structure:                                                                
 ##STR97##                                                                
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR98##                                                                
Crystalline form: Colorless amorphous                                     
NMR analysis: 17)                                                         
Form: Free                                                                
Example 54                                                                
Structure:                                                                
 ##STR99##                                                                
R.sup.2 : NHCH.sub.3 (5-position)                                         
R.sup.3 : H                                                               
 ##STR100##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 213-216° C.                                         
Form: Free                                                                
Example 55                                                                
Structure:                                                                
 ##STR101##                                                               
R.sup.2 : N(CH.sub.3).sub.2 (5-position)                                  
R.sup.3 : H                                                               
 ##STR102##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 18)                                                         
Form: Free                                                                
Example 56                                                                
Structure:                                                                
 ##STR103##                                                               
R.sup.2 : CH.sub.2 (5-position)                                           
R.sup.3 : H                                                               
 ##STR104##                                                               
Crystalline form: Yellow amorphous                                        
NMR analysis: 19)                                                         
Form: Free                                                                
Example 57                                                                
Structure:                                                                
 ##STR105##                                                               
R.sup.2 : O (5-position)                                                  
R.sup.3 : H                                                               
 ##STR106##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 20)                                                         
Form: Free                                                                
Example 58                                                                
Structure:                                                                
 ##STR107##                                                               
R.sup.2 : CH.sub.2 CO.sub.2 CH.sub.3 (5-position)                         
R.sup.3 : H                                                               
 ##STR108##                                                               
Crystalline form: White powder                                            
NMR analysis: 21)                                                         
Form: Free                                                                
Example 59                                                                
Structure:                                                                
 ##STR109##                                                               
R.sup.2 : OCH.sub.2 CO.sub.2 CH.sub.3 (5-position)                        
R.sup.3 : H                                                               
 ##STR110##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 182-184° C.                                         
Form: Free                                                                
Example 60                                                                
Structure:                                                                
 ##STR111##                                                               
R.sup.2 : OCH.sub.2 COOH (5-position)                                     
R.sup.3 : H                                                               
 ##STR112##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Diethyl ether                                  
Melting point: 220-222° C.                                         
Form: Free                                                                
Example 61                                                                
Structure:                                                                
 ##STR113##                                                               
R.sup.2 : OCH.sub.2 CH.sub.2 OSO.sub.2 CH.sub.3 (5-position)              
R.sup.3 : H                                                               
 ##STR114##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 22)                                                         
Form: Free                                                                
Example 62                                                                
Structure:                                                                
 ##STR115##                                                               
 ##STR116##                                                               
R.sup.3 : H                                                               
 ##STR117##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 23)                                                         
Form: Free                                                                
Example 63                                                                
Structure:                                                                
 ##STR118##                                                               
R.sup.2 : OCH.sub.2 CH.sub. 2 NH.sub.2 (5-position)                       
R.sup.3 : H                                                               
 ##STR119##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 24)                                                         
Form: Free                                                                
Example 64                                                                
Structure:                                                                
 ##STR120##                                                               
R.sup.2 : O (5-position)                                                  
R.sup.3 : H                                                               
 ##STR121##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 207-210° C.                                         
Form: Free                                                                
Example 65                                                                
Structure:                                                                
 ##STR122##                                                               
R.sup.2 : O (5-position)                                                  
R.sup.3 : H                                                               
 ##STR123##                                                               
Crystalline form: Yellow powder                                           
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 225-228° C.                                         
Form: Free                                                                
Example 66                                                                
Structure:                                                                
 ##STR124##                                                               
R.sup.2 : O (5-position)                                                  
R.sup.3 : H                                                               
 ##STR125##                                                               
Crystalline form: Yellow powder                                           
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 182.5-185.5° C.                                     
Form: Free                                                                
Example 67                                                                
Structure:                                                                
 ##STR126##                                                               
R.sup.2 : O (5-position)                                                  
R.sup.3 : H                                                               
 ##STR127##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 183-184.5° C.                                       
Form: Free                                                                
Example 68                                                                
Structure:                                                                
 ##STR128##                                                               
R.sup.2 : O (5-position)                                                  
R.sup.3 : H                                                               
 ##STR129##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 160-162° C.                                         
Form: Free                                                                
Example 69                                                                
Structure:                                                                
 ##STR130##                                                               
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR131##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 25)                                                         
Form: Free                                                                
Example 70                                                                
Structure:                                                                
 ##STR132##                                                               
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR133##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane - methanol                     
Melting point: 153-155° C.                                         
Form: Free                                                                
Example 71                                                                
Structure:                                                                
 ##STR134##                                                               
R.sup.2 : OCH.sub.3 (5-position)                                          
R.sup.3 : H                                                               
 ##STR135##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 171-174° C.                                         
Form: Free                                                                
Example 72                                                                
Structure:                                                                
 ##STR136##                                                               
R.sup.2 : OCH.sub.3 (5-position)                                          
R.sup.3 : H                                                               
 ##STR137##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 176-178° C.                                         
Form: Free                                                                
Example 73                                                                
Structure:                                                                
 ##STR138##                                                               
R.sup.2 : OCH.sub.3 (5-position)                                          
R.sup.3 : H                                                               
 ##STR139##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 184-186° C.                                         
Form: Free                                                                
Example 74                                                                
Structure:                                                                
 ##STR140##                                                               
R.sup.2 : OCH.sub.2 CHCH.sub.2 (5-position)                               
R.sup.3 : H                                                               
 ##STR141##                                                               
Crystalline form: White powder                                            
NMR analysis: 54)                                                         
Form: Free                                                                
Example 75                                                                
Structure:                                                                
 ##STR142##                                                               
R.sup.2 : OCH.sub.2 CHCH.sub.2 (5-position)                               
R.sup.3 : H                                                               
 ##STR143##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 152-154° C.                                         
Form: Free                                                                
Example 76                                                                
Structure:                                                                
 ##STR144##                                                               
R.sup.2 : OCH.sub.2 CHCH.sub.2 (5-position)                               
R.sup.3 : H                                                               
 ##STR145##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 183-186° C.                                         
Form: Free                                                                
Example 77                                                                
Structure:                                                                
 ##STR146##                                                               
 ##STR147##                                                               
R.sup.3 : H                                                               
 ##STR148##                                                               
Crystalline form: White powder                                            
NMR analysis: 55)                                                         
Form: Free                                                                
Example 78                                                                
Structure:                                                                
 ##STR149##                                                               
 ##STR150##                                                               
R.sup.3 : H                                                               
 ##STR151##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 162-165° C.                                         
Form: Free                                                                
Example 79                                                                
Structure:                                                                
 ##STR152##                                                               
R.sup.2 : NHCH.sub.3 (5-position)                                         
R.sup.3 : H                                                               
 ##STR153##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 172-175° C.                                         
Form: Free                                                                
Example 80                                                                
Structure:                                                                
 ##STR154##                                                               
R.sup.2 : NHCH.sub.3 (5-position)                                         
R.sup.3 : H                                                               
 ##STR155##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 162-165° C.                                         
Form: Free                                                                
Example 81                                                                
Structure:                                                                
 ##STR156##                                                               
R.sup.2 : N(CH.sub.3).sub.2 (5-position)                                  
R.sup.3 : H                                                               
 ##STR157##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 200-202° C.                                         
Form: Free                                                                
Example 82                                                                
Structure:                                                                
 ##STR158##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR159##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 187-189° C.                                         
Form: Free                                                                
Example 83                                                                
Structure:                                                                
 ##STR160##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR161##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 213-216° C.                                         
Form: Free                                                                
Example 84                                                                
Structure:                                                                
 ##STR162##                                                               
R.sup. 2 : H                                                              
R.sup.3 : H                                                               
 ##STR163##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 122-125° C.                                         
Form: Free                                                                
Example 85                                                                
Structure:                                                                
 ##STR164##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR165##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane -diethyl ether                 
Melting point: 155-157° C.                                         
Form: Free                                                                
Example 86                                                                
Structure:                                                                
 ##STR166##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR167##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 182-184° C.                                         
Form: Free                                                                
Example 87                                                                
Structure:                                                                
 ##STR168##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR169##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 157-158.5° C.                                       
Form: Free                                                                
Example 88                                                                
Structure:                                                                
 ##STR170##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR171##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 111-114° C.                                         
Form: Free                                                                
Example 89                                                                
Structure:                                                                
 ##STR172##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR173##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 127-130° C.                                         
Form: Free                                                                
Example 90                                                                
Structure:                                                                
 ##STR174##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR175##                                                               
Crystalline form: White powder                                            
NMR analysis: 26)                                                         
Form: Free                                                                
Example 91                                                                
Structure:                                                                
 ##STR176##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR177##                                                               
Crystalline form: White powder                                            
NMR analysis: 27)                                                         
Form: 2 HCl                                                               
Example 92                                                                
Structure:                                                                
 ##STR178##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR179##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 159-162° C.                                         
Form: Free                                                                
 Example 93                                                               
Structure:                                                                
 ##STR180##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR181##                                                               
Crystalline form: White powder                                            
NMR analysis: 28)                                                         
Form: Free                                                                
Example 94                                                                
Structure:                                                                
 ##STR182##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR183##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Ethyl acetate                                  
Melting point: 176-179° C.                                         
Form: Free                                                                
*)This compound is obtained only by the process of Example 17.            
Example 95                                                                
Structure:                                                                
 ##STR184##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR185##                                                               
Crystalline form: White powder                                            
NMR analysis: 29)                                                         
Form: Free                                                                
Example 96                                                                
Structure:                                                                
 ##STR186##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR187##                                                               
Crystalline form: White powder                                            
NMR analysis: 30)                                                         
Form: 2 HCl                                                               
Example 97                                                                
Structure:                                                                
 ##STR188##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR189##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 204-207° C.                                         
Form: Free                                                                
Example 98                                                                
Structure:                                                                
 ##STR190##                                                               
R.sup.2 : CH.sub.2 CO.sub.2 CH.sub.3 (5-position)                         
R.sup.3 : H                                                               
 ##STR191##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 167-170° C.                                         
Form: Free                                                                
Example 99                                                                
Structure:                                                                
 ##STR192##                                                               
R.sup.2 : CH.sub.2 COOH (5-position)                                      
R.sup.3 : H                                                               
 ##STR193##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 224-227° C.                                         
Form: Free                                                                
Example 100                                                               
Structure:                                                                
 ##STR194##                                                               
R.sup.2 : CH.sub.2 COOCH.sub.3 (5-position)                               
R.sup.3 : H                                                               
 ##STR195##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 185-188° C.                                         
Form: Free                                                                
Example 101                                                               
Structure:                                                                
 ##STR196##                                                               
R.sup.2 : CH.sub.2 COOH (5-position)                                      
R.sup.3 : H                                                               
 ##STR197##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Ethyl acetate-diethyl ether                    
Melting point: 221-223° C.                                         
Form: Free                                                                
Example 102                                                               
Structure:                                                                
 ##STR198##                                                               
R.sup.2 : CH.sub.2 CONHCH.sub.3 (5-position)                              
R.sup.3 : H                                                               
 ##STR199##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 134-137° C.                                         
Form: Free                                                                
Example 103                                                               
Structure:                                                                
 ##STR200##                                                               
R.sup.2 : CH.sub.2 CONHC.sub.2 H.sub.5 (5-position)                       
R.sup.3 : H                                                               
 ##STR201##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 196-199° C.                                         
Form: Free                                                                
Example 104                                                               
Structure:                                                                
 ##STR202##                                                               
 ##STR203##                                                               
R.sup.3 : H                                                               
 ##STR204##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 254-256° C.                                         
Form: Free                                                                
Example 105                                                               
Structure:                                                                
 ##STR205##                                                               
 ##STR206##                                                               
R.sup.3 : H                                                               
 ##STR207##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 156-158° C.                                         
Form: Free                                                                
Example 106                                                               
Structure:                                                                
 ##STR208##                                                               
 ##STR209##                                                               
R.sup.3 : H                                                               
 ##STR210##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 31)                                                         
Form: Free                                                                
Example 107                                                               
Structure:                                                                
 ##STR211##                                                               
 ##STR212##                                                               
R.sup.3 : H                                                               
 ##STR213##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 222-225° C.                                         
Form: Free                                                                
Example 108                                                               
Structure:                                                                
 ##STR214##                                                               
 ##STR215##                                                               
R.sup.3 : H                                                               
 ##STR216##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 229-232° C.                                         
Form: Free                                                                
Example 109                                                               
Structure:                                                                
 ##STR217##                                                               
 ##STR218##                                                               
R.sup.3 : H                                                               
 ##STR219##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 152-154° C.                                         
Form: Free                                                                
Example 110                                                               
Structure:                                                                
 ##STR220##                                                               
R.sup.2 : CH.sub.2 CON(CH.sub.3).sub.2 (5-position)                       
R.sup.3 : H                                                               
 ##STR221##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 216-217° C.                                         
Form: Free                                                                
Example 111                                                               
Structure:                                                                
 ##STR222##                                                               
R.sup.2 : CH.sub.2 CONHCH.sub.3 (5-position)                              
R.sup.3 : H                                                               
 ##STR223##                                                               
Crystalline form: White powder                                            
NMR analysis: 56)                                                         
Form: Free                                                                
Example 112                                                               
Structure:                                                                
 ##STR224##                                                               
R.sup.2 : CH.sub.2 CONHC.sub.2 H.sub.5 (5-position)                       
R.sup.3 : H                                                               
 ##STR225##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 203- 205° C.                                        
Form: Free                                                                
Example 113                                                               
Structure:                                                                
 ##STR226##                                                               
 ##STR227##                                                               
R.sup.3 : H                                                               
 ##STR228##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 191-193.5° C.                                       
Form: Free                                                                
Example 114                                                               
Structure:                                                                
 ##STR229##                                                               
 ##STR230##                                                               
R.sup.3 : H                                                               
 ##STR231##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 191-193° C.                                         
Form: Free                                                                
Example 115                                                               
Structure:                                                                
 ##STR232##                                                               
 ##STR233##                                                               
R.sup.3 : H                                                               
 ##STR234##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 32)                                                         
Form: Free                                                                
Example 116                                                               
Structure:                                                                
 ##STR235##                                                               
 ##STR236##                                                               
R.sup.3 : H                                                               
 ##STR237##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Ethyl acetate - diethyl ether                  
Melting point: 157-160° C.                                         
Form: Free                                                                
Example 117                                                               
Structure:                                                                
 ##STR238##                                                               
R.sup.2 : CH.sub.2 CONH.sub.2 (5-position)                                
R.sup.3 : H                                                               
 ##STR239##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 242-244° C.                                         
Form: Free                                                                
Example 118                                                               
Structure:                                                                
 ##STR240##                                                               
 ##STR241##                                                               
R.sup.3 : H                                                               
 ##STR242##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 223-225.5° C.                                       
Form: Free                                                                
Example 119                                                               
Structure:                                                                
 ##STR243##                                                               
R.sup.2 : CH.sub.2 CON(CH.sub.3).sub.2 (5-position)                       
R.sup.3 : H                                                               
 ##STR244##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 224-225° C.                                         
Form: Free                                                                
Example 120                                                               
Structure:                                                                
 ##STR245##                                                               
 ##STR246##                                                               
R.sup.3 : H                                                               
 ##STR247##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 145-147° C.                                         
Form: Free                                                                
Example 121                                                               
Structure:                                                                
 ##STR248##                                                               
R.sup.2 : (CH.sub.2).sub.2 OH (5-position)                                
R.sup.3 : H                                                               
 ##STR249##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 161-163° C.                                         
Form: Free                                                                
Example 122                                                               
Structure:                                                                
 ##STR250##                                                               
R.sup.2 : (CH.sub. 2).sub.2 OCOCH.sub.3 (5-position)                      
R.sup.3 : H                                                               
 ##STR251##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 151-153° C.                                         
Form: Free                                                                
Example 123                                                               
Structure:                                                                
 ##STR252##                                                               
R.sup.2 : (CH.sub.2).sub.2 OH (5-position)                                
R.sup.3 : H                                                               
 ##STR253##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 168-170° C.                                         
Form: Free                                                                
Example 124                                                               
Structure:                                                                
 ##STR254##                                                               
R.sup.2 : (CH.sub.2).sub.2 OCOCH.sub.3 (5-position)                       
R.sup.3 : H                                                               
 ##STR255##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 150-153° C.                                         
Form: Free                                                                
Example 125                                                               
Structure:                                                                
 ##STR256##                                                               
R.sup.2 : (CH.sub.2).sub.2 OSO.sub.2 CH.sub.3 (5-position)                
R.sup.3 : H                                                               
 ##STR257##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 33)                                                         
Form: Free                                                                
Example 126                                                               
Structure:                                                                
 ##STR258##                                                               
 ##STR259##                                                               
R.sup.3 : H                                                               
 ##STR260##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 34)                                                         
Form: Free                                                                
Example 127                                                               
Structure:                                                                
 ##STR261##                                                               
 ##STR262##                                                               
R.sup.3 : H                                                               
 ##STR263##                                                               
Crystalline form: Yellow amorphous                                        
NMR analysis: 35)                                                         
Form: Free                                                                
Example 128                                                               
Structure:                                                                
 ##STR264##                                                               
 ##STR265##                                                               
R.sup.3 : H                                                               
 ##STR266##                                                               
Crystalline form: Yellow amorphous                                        
NMR analysis: 36)                                                         
Form: Free                                                                
Example 129                                                               
Structure:                                                                
 ##STR267##                                                               
 ##STR268##                                                               
R.sup.3 : H                                                               
 ##STR269##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 201-204° C.                                         
Form: Free                                                                
Example 130                                                               
Structure:                                                                
 ##STR270##                                                               
R.sup.2 : (CH.sub.2).sub.2 NHCH(CH.sub.3).sub.2 (5-position)              
R.sup.3 : H                                                               
 ##STR271##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 37)                                                         
Form: Free                                                                
Example 131                                                               
Structure:                                                                
 ##STR272##                                                               
 ##STR273##                                                               
R.sup.3 : H                                                               
 ##STR274##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 38)                                                         
Form: Free                                                                
Example 132                                                               
Structure:                                                                
 ##STR275##                                                               
R.sup.2 : (CH.sub.2).sub.2 NH.sub.2 (5-position)                          
R.sup.3 : H                                                               
 ##STR276##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 39)                                                         
Form: Free                                                                
Example 133                                                               
Structure:                                                                
 ##STR277##                                                               
R.sup.2 : (CH.sub.2).sub.2 N(CH.sub.3).sub.2 (5-position)                 
R.sup.3 : H                                                               
 ##STR278##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 40)                                                         
Form: Free                                                                
Example 134                                                               
Structure:                                                                
 ##STR279##                                                               
R.sup.2 : (CH.sub.2).sub.2 OSO.sub.2 CH.sub.3 (5-position)                
R.sup.3 : H                                                               
 ##STR280##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 41)                                                         
Form: Free                                                                
Example 135                                                               
Structure:                                                                
 ##STR281##                                                               
 ##STR282##                                                               
R.sup.3 : H                                                               
 ##STR283##                                                               
Crystalline form: Yellow amorphous                                        
NMR analysis: 42)                                                         
Form: Free                                                                
Example 136                                                               
Structure:                                                                
 ##STR284##                                                               
 ##STR285##                                                               
R.sup.3 : H                                                               
 ##STR286##                                                               
Crystalline form: Yellow amorphous                                        
NMR analysis: 43)                                                         
Form: Free                                                                
Example 137                                                               
Structure:                                                                
 ##STR287##                                                               
 ##STR288##                                                               
R.sup.3 : H                                                               
 ##STR289##                                                               
Crystalline form: Yellow amorphous                                        
NMR analysis: 44)                                                         
Form: Free                                                                
Example 138                                                               
Structure:                                                                
 ##STR290##                                                               
 ##STR291##                                                               
R.sup.3 : H                                                               
 ##STR292##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting Point: 192-195° C.                                         
Form: Free                                                                
 Example 139                                                              
Structure:                                                                
 ##STR293##                                                               
R.sup.2 : (CH.sub.2).sub.2 NHCH(CH.sub.3).sub.2 (5-position)              
R.sup.3 : H                                                               
 ##STR294##                                                               
Crystalline form: Yellow amorphous                                        
NMR analysis: 45)                                                         
Form: Free                                                                
Example 140                                                               
Structure:                                                                
 ##STR295##                                                               
 ##STR296##                                                               
R.sup.3 : H                                                               
 ##STR297##                                                               
Crystalline form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 149-152° C.                                         
Form: Free                                                                
Example 141                                                               
Structure:                                                                
 ##STR298##                                                               
 ##STR299##                                                               
R.sup.3 : H                                                               
 ##STR300##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 46)                                                         
Form: Free                                                                
Example 142                                                               
Structure:                                                                
 ##STR301##                                                               
R.sup.2 : (CH.sub.2).sub.2 NH.sub.2 (5-position)                          
R.sup.3 : H                                                               
 ##STR302##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 47)                                                         
Form: Free                                                                
Example 143                                                               
Structure:                                                                
 ##STR303##                                                               
R.sup.2 : (CH.sub.2).sub.2 NHCOCH.sub.3 (5-position)                      
R.sup.3 : H                                                               
 ##STR304##                                                               
Crystalline form: White powder                                            
NMR analysis: 48)                                                         
Form: Free                                                                
Example 144                                                               
Structure:                                                                
 ##STR305##                                                               
R.sup.2 : CH.sub.2 (5-position)                                           
R.sup.3 : H                                                               
 ##STR306##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 49)                                                         
Form: Free                                                                
Example 145                                                               
Structure:                                                                
 ##STR307##                                                               
R.sup.2 : OH (5-position)                                                 
R.sup.3 : CH.sub.2 OH (5-position)                                        
 ##STR308##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 50)                                                         
Form: Free                                                                
Example 146                                                               
Structure:                                                                
 ##STR309##                                                               
R.sup.2 : OCH.sub.3 (4-position)                                          
R.sup.3 : OCH.sub.3 (4-position)                                          
 ##STR310##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 51)                                                         
Form: Free                                                                
Example 147                                                               
Structure:                                                                
 ##STR311##                                                               
R.sup.2 : O (4-position)                                                  
R.sup.3 : H                                                               
 ##STR312##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 52)                                                         
Form: Free                                                                
Example 148                                                               
Structure:                                                                
 ##STR313##                                                               
R.sup.2 : OH (4-position)                                                 
R.sup.3 : H                                                               
 ##STR314##                                                               
Crystalline form: Colorless amorphous                                     
NMR analysis: 53)                                                         
Form: Free                                                                
______________________________________
TABLE 2
1) 1 H-NMR (CDCl3) δ: 1.60-2.60 (4H, m), 2.46 (3H, s), 2.70-2.95 (1H, m), 3.73 (1H, s), 4.65-5.65 (2H, m), 6.57 (1H, d, J=8.1 Hz), 7.00 (1H, d, J=6.5 Hz), 7.15-8.40 (8H, m), 8.70-8.90 (1H, m)
2) 1 H-NMR (CDCl3) δ: 1.60-2.45 (4H, m), 2.41 (3H, s), 2.70-3.30 (2H, m), 4.65-5.70 (2H, m), 6.60 (1H, d, J=8.4 Hz), 7.01 (1H, dd, J=2, 8.1 Hz), 7.20-7.50 (2H, m), 7.50-7.90 (4H, m), 8.05-8.40 (2H, m), 8.72 (1H, s)
3) 1 H-NMR (CDCl3) δ: 1.60-2.45 (4H, m), 2.41 (3H, s), 2.70-2.90 (1H, m), 3.20-3.60 (1H, m), 4.65-5.70 (2H, m), 6.59 (1H, d, J=8.2 Hz), 7.00 (1H, dd, J=2, 8.1 Hz), 7.15-7.30 (2H, m), 7.50-7.85 (4H, m), 8.05-8.40 (2H, m), 8.77 (1H, s)
4) 1 H-NMR (CDCl3) δ: 1.60-2.90 (6H, m), 4.06 (3H, s), 4.75-5.20 (2H, m), 6.61 (1H, d, J=8 Hz), 6.95-7.25 (3H, m), 7.45-7.85 (3H, m), 8.10-8.50 (3H, m), 10.39 (1H, s)
5) 1 H-NMR (CDCl3) δ:1.50-2.50 (4H, m), 2.60-2.90 (1H, m), 3.40-3.70 (1H, m), 4.60-5.20 (2H, m), 6.56 (1H, d, J=8.2 Hz), 7.01 (1H, dd, J=2.1, 8.3 Hz), 7.20-7.90 (6H, m), 7.90-8.20 (2H, m), 9.29 (1H, s)
6) 1 H-NMR (CDCl3) δ:1.55-2.60 (4H, m), 2.65-2.95 (1H, m), 3.20-3.60 (1H, m), 4.70-5.25 (2H, m), 6.58 (1H, d, J=8.2 Hz), 7.01 (1H, d, J=8.1 Hz), 7.10-7.90 (6H, m), 7.90-8.40 (2H, m), 9.04 (1H, s)
7) 1 H-NMR (CDCl3) δ:1.60-2.50 (4H, m), 2.70-2.90 (1H, m), 3.40-3.80 (1H, m), 4.70-5.20 (2H, m), 6.59 (1H, d, J=8.3 Hz), 7.00 (1H, dd, J=2.3, 8.3 Hz), 7.10-7.15 (1H, m), 7.55-7.60 (2H, m), 7.60-7.85 (2H, m), 8.00-8.40 (2H, m), 8.81 (1H, s)
8) 1 H-NMR (CDCl3) δ:1.20-2.40 (15H, m), 2.70-3.00 (1H, m), 3.20-3.40 (1H, m), 4.70-5.20 (2H, m), 6.57 (1H, d, J=8.3 Hz), 7.00 (1H, d, J=8.4 Hz), 7.47 (1H, d, J=8.8 Hz), 7.71 (1H, s), 8.00-8.35 (3H, m)
9) 1 H-NMR (CDCl3) δ:1.60-2.40 (4H, m), 2.30 (3H, s), 2.65-3.10 (2H, m), 3.74 (2H, s), 4.70-5.15 (2H, m), 6.54 (1H, d, J=8.3 Hz), 6.97 (1H, dd, J=2.1, 8.3 Hz), 7.20-7.30 (4H, m), 7.45-7.85 (2H, m), 7.88 (1H, s), 7.90-8.30 (2H, m)
10) 1 H-NMR (CDCl3) δ:1.50-2.60 (3H, m), 2.45 (3H, s), 2.60-2.95 (1H, m), 3.60-4.25 (4H, m), 4.70-5.10 (1H, m), 6.54 (1H, d, J=8.3 Hz), 6.99 (1H, dd, J=2.3, 8.3 Hz), 7.10-7.70 (5H, m), 7.82 (1H, d, J=2.3 Hz), 8.10-8.30 (2H, m), 8.83 s) (1H, s)
11) 1 H-NMR (CDCl3) δ:1,60-2.60 (8H, m), 2.29, 2.32 (3H, s), 2.50 (3H, s), 2.70-3.05 (1H, m), 3.40-3.80 (4H, m), 4.10-4.50 (2H, m), 4.55-5.20 (2H, m), 6.60-6.75 (1H, m), 7.00-7.15 (1H, m), 7.15-7.85 (6H, m), 8.10-8.40 (3H, m)
12) 1 H-NMR (CDCl3) δ:1.50-2.60 (4H, m), 2.51 (3H, s), 2.70-3.05 (1H, m), 3.50-4.05 (4H, m), 4.50-5.15 (2H, m), 6.60-6.75 (1H, m), 7.00-7.15 (1H, m), 7.20-7.85 (6H, m), 8.10-8.40 (3H, m)
13) 1 H-NMR (CDCl3) δ:1.50-3.00 (13H, m), 2.50 (3H, s), 3.40-3.85 (2H, m), 4.45-5.15 (2H, m), 6.60 (1H, d, J=8.1 Hz), 7.00-7.10 (1H, m), 7.20-7.90 (6H, m), 8.05-8.60 (3H, m)
14) 1 H-NMR (CDCl3) δ:1.60-2.70 (6H, m), 2.50 (3H, s), 2.70-3.00 (1H, m), 3.00-3.20 (1H, m), 3.40-3.80 (4H, m), 4.50-5.10 (2H, m), 5.95-6.15 (1H, m), 6.65-6.80 (1H, m), 7.00-7.20 (1H, m), 7.20-7.80 (6H, m), 8.05-8.50 (3H, m)
15) 1 H-NMR (CDCl3) δ:1.20-3.95 (16H, m), 2.34 (3H, s), 2.50 (3H, s), 4.40-5.15 (1H, m), 6.61 (1H, d, J=8.3 Hz), 6.97 (1H, dd, J=2.1,8.3 Hz), 7.03 (1H, s), 7.20-7.40 (3H, m), 7.48 (1H, d, J=7.6 Hz), 7.83 (1H, dd, J=2.1, 8.8 Hz), 8.20 (1H, d, J=8.8 Hz), 8.31 (1H, s), 8.38 (1H, d, J=2.1 Hz)
16) 1 H-NMR (CDCl3) δ:2.43 (3H, s), 2.49 (3H, s), 3.04 (3H, s), 3.70 (1H, d, J=14 Hz), 4.02 (1H, d, J=14 Hz), 4.85-5.10 (1H, m), 6.61 (1H, d, J=8.3 Hz), 7.03 (1H, dd, J=2.4, 8.3 Hz), 7.20-7.60 (6H, m), 8.01 (1H, d, J=1.7 Hz), 8.12 (1H, d, J=8.7 Hz), 8.67 (1H, s)
17) 1 H-NMR (CDCl3) δ:1.75-2.20 (2H, m), 2.80-3.30 (2H, m), 2.96 (3H, s), 3.40-3.65 (1H, m), 4.45-4.70 (1H, m), 6.52 (1H, d, J=8.2 Hz), 6.62 (1H, dd, J=1.8, 8.2 Hz), 6.90 (1H, d, J=1.9 Hz), 7.30-7.55 (4H, m), 7.66 (1H, d, J=7.1 Hz), 7.95 (1H, d, J=1.6 Hz), 8.16 (1H, d, J=8.6 Hz), 9.14 (1H, s)
18) 1 H-NMR (CDCl3) δ:1.20-2.60 (10H, m), 2.44 (3H, s), 3.15-3.65 (2H, m), 4.00-5.00 (1H, m), 6.50 (2H, s), 6.90-7.50 (6H, m), 7.67 (1H, s), 8.73 (1H, s)
19) 1 H-NMR (CDCl3) δ: 1.85-2.20 (2H, m), 2.30-3.30 (3H, m), 2.50 (3H, s), 4.75-5.15 (1H, m), 5.20-5.35 (2H, m), 6.61 (1H, d, J=8.3 Hz), 7.01 (1H, dd, J=2.5, 8.4 Hz), 7.20-7.60 (6H, m), 8.06 (1H, d, J=2 Hz), 8.19 (1H, d, J=8.7 Hz), 8.34 (1H, s)
20) 1 H-NMR (CDCl3) δ:2.00-2.40 (2H, m), 2.30 (3H, s), 2.85 (2H, t, J=6.2 Hz), 3.74 (2H, s), 3.40-4.60 (2H, m), 6.66 (1H, d, J=8.4 Hz), 7.15-7.30 (5H, m), 7.52 (1H, dd, J=2.4, 8.6 Hz), 7.74 (1H, s), 7.82 (1H, d, J=2.5 Hz), 8.05-8.15 (2H, m)
21 ) 1 H-NMR (CDCl3) δ:1.60-2.60 (4H, m), 2.51 (3H, s), 3.70-3.80 (3H, m), 4.10-4.50 (2H, m), 4.55-5.20 (2H, m), 6.60-6.70 (1H, m), 7.00-7.15 (1H, m), 7.20-7.90 (6H, m), 8.10-8.45 (3H, m)
22) 1 H-NMR (CDCl3) δ:1.50-2.60 (4H, m), 2.50 (3H, s), 2.70-3.20 (1H, m), 2.93, 3.13 (3H, s), 3.70-4.05 (2H, m), 4.20-5.20 (4H, m), 6.64 (1H, d, J=8.1 Hz), 7.00-7.10 (1H, m), 7.20-7.85 (6H, m), 8.05-8.40 (3H, m)
23) 1 H-NMR (CDCl3) δ:1.45-2.55 (4H, m), 2.51 (3H, s), 2.60-2.95 (1H, m), 3.70-4.20 (2H, m), 4.50-5.15 (2H, m), 6.58 (1H, d, J=8.2 Hz), 6.99 (1H, d J=8.5 Hz), 7.20-8.50 (15H, m)
24) 1 H-NMR (CDCl3) δ: 1.50-2.60 (4H, m), 2.50 (3H, s), 2.65-3.20 (3H, m), 3.40-3.80 (2H, m), 4.45-5.15 (2H, m), 6.62 (1H, d, J=8.1 Hz), 7.04 (1H,d, J=8.1 Hz), 7.15-7.85 (6H, m), 8.10-8.50 (3H, m)
25) 1 H-NMR (CDCl3) δ:1.60-2.50 (3H, m), 2.65-2.90 (1H, m), 3.20- 3.35 (1H, m), 3.81 (3H, s), 4.70-5.15 (2H, m), 6.57 (1H, d, J=8.3 Hz), 7.01 (1H, d, J=8.2 Hz), 7.20-8.25 (8H, m), 8.85-9.15 (1H, m)
26) 1 H-NMR (CDCl3) δ:1.40-1.70 (1H, m), 1.85-2.20 (3H, m), 2.70-3.15 (3H, m), 3.06 (3H, s), 4.45-4.55 (2H, m), 4.60-4.70 (2H, m), 4.95-5.15 (1H, m), 6.62 (1H, d, J=8.2 Hz), 6.97 (2H, t, J=8.2 Hz), 7.17 (1H, t, J=7.2 Hz), 7.28 (1H, s), 7.45-7.60 (2H, m), 8.09 (1H, s), 8.15-8.30 (2H, m), 10.23 (1H, s)
27) 1 H-NMR (DMSO-d6) δ:1.18 (6H, d, J=6.4 Hz), 1.30-1.60 (1H, m), 1.70-2.15 (3H, m), 2.10-3.20 (3H, m), 3.20-3.55 (3H, m), 4.40-4.55 (2H, m), 4.75-4.95 (1H, m), 6.89 (1H, d, J=8.4 Hz), 7.05-7.25 (3H, m), 7.45-7.80 (4H, m), 8.01 (1H, s), 8.11 (1H, d, J=8.6 Hz), 9.27 (2H, brs), 10.71 (1H, s)
28) 1 H-NMR (CDCl3) δ:1.30-1.65 (1H, m), 1.90-2.20 (3H, m), 2.60-3.10 (3H, m), 4.10-4.30 (2H, m), 4.40-4.60 (2H, m), 4.90-5.10 (1H, m), 6.60 (1H, d, J=8 Hz), 6.90-7.00 (1H, m), 7.00-7.15 (2H, m), 7.25-7.30 (1H, m), 7.40-7.55 (2H, m), 7.60-7.85 (4H, m), 7.97 (1H, s), 8.10-8.20 (2H, m), 10.05 (1H, s)
29) 1 -NMR (CDCl3) δ: 1.35-2.20 (4H, m), 2.60-3.40 (5H, m), 4.15-4.30 (2H, m), 4.90-5.10 (1H, m), 6.61 (1H, d, J=8.2 Hz), 6.90-7.30 (4H, m), 7.40-7.55 (2H, m), 8.15-8.25 (3H, m), 10.81 (1H, s)
30) 1 H-NMR (DMSO-d6) δ:1.30-1.60 (1H, m), 1.80-2.15 (3H, m), 2.79 (6H, s), 2.60-3.20 (3H, m), 3.55 (2H, s), 4.53 (2H, s), 4.75-4.90 (1H, m), 5.60 (1H, brs), 6.87 (1H, d, J=8.4 Hz), 7.05-7.25 (3H, m), 7.45-7.75 (4H, m), 8.05-8.15 (2H, m), 10.69 (1H, s), 10.90 (1H, brs)
31) 1 H-NMR (CDCl3) δ: 1.30-2.15 (4H, m), 2.49 (3H, s), 2.62 (6H, s), 2.30-3.90 (8H, m), 4.35-4.55, 5.10-5.30 (1H, m), 6.60 (1H, d, J=8.3 Hz), 6.90-7.05 (1H, m), 7.20-7.80 (7H, m), 8.15 (1H, d, J=8.5 Hz), 8.30-8.40 (2H, m)
32) 1 H-NMR (CDCl3) δ:1.30-2.10 (4H, m), 1.49 (9H, s), 2.60-3.95 (12H, m), 4.40-4.60, 5.05-5.20 (1H, m), 6.58 (1H, d, J=8.2 Hz), 6.90-7.05 (2H, m), 7.30-7.50 (3H, m), 7.60-7.90 (2H, m), 8.00-8.25 (1H, m), 8.35 (1H, d, J=2 Hz), 8.75 (1H, s)
33) 1 H-NMR (CDCl3) δ: 1.30-2.50 (6H, m), 2.55-3.45 (2H, m), 3.04 (3H, s), 4.20-4.60, 5.10-5.25 (3H, m), 6.64 (1H, d, J=8.3 Hz), 7.03 (1H, d, J=8.2 Hz), 7.15-7.50 (5H, m), 7.56 (1H, d, J=8.6 Hz), 7.72 (1H, d, J=6.2 Hz), 8.09 (1H, s), 8.21 (1H, d, J=8.7 Hz), 8.74 (1H, s)
34) 1 H-NMR (CDCl3) δ:1.30-2.80 (14H, m), 3.05-3,40 (2H, m), 4.25-4.45, 5.05-5.25 (1H, m), 6.60 (1H, d, J=8.2 Hz), 6.90-7.05 (1H, m), 7.25-7.60 (5H, m), 7.72 (1H, d, J=6.4 Hz), 8.17 (1H, d, J=8.1 Hz), 8.70 (1H, s)
35) 1 H-NMR (CDCl3) δ:1.30-2.80 (12H, m), 3.05-3.40 (2H, m), 3.60-3.90 (4H, m), 4.30-4.60, 5.05-5.25 (1H, m), 6.61 (1H, d, J=8.2 Hz), 6.90-7.10 (1H, m), 7.20-7.70 (5H, m), 7.72 (1H, d, J=6.2 Hz), 8.10-8.30 (2H, m), 8.69 (1l H, s)
36) 1 H-NMR (CDCl3) δ:1.25-2.30 (6H, m), 2.07 (3H, s), 2.30-2.80 (6H, m), 3.00-3.70 (6H, m), 4.30-4.50, 5.10-5.25 (1H, m), 6.55-6.64 (1H, m), 6.90-7.05 (1H, m), 7.20-7.30 (1H, m), 7.40-7.50 (3H, m), 7.55-7.65 (1H, m), 7.73 (1H, d, J=6.3 Hz), 8.10-8.25 (2H, m), 8.68 (1H, s)
37) 1 H-NMR (CDCl3) δ:1.04-1.12 (6H, m), 1.20-2.30 (6H, m), 2.50-3.00 (3H, m), 3.00-3.40 (2H, m), 4.30-4.50, 5.10-5.25 (1H, m), 6.50-6.65 (1H, m), 6.90-7.15 (1H, m), 7.25-7.65 (5H, m), 7.73 (1H, d, J=7.2 Hz), 8.17 (1H, d, J=8.9 Hz), 8.70 (1H, brs)
38) 1 H-NMR (CDCl3) δ: 1.25-2.50 (6H, m), 2.60-3.40 (2H, m), 3.70-4.00 (2H, m), 4.30-4.50, 5.10-5.30 (1H, m), 6.62 (1H, d, J=8.5 Hz), 6.90-7.15 (1H, m), 7.25-7.60 (5H, m), 7.65-7.90 (5H, m), 8.00-8.30 (2H, m), 8.72 (1H, s)
39) 1 H-NMR (CDCl3) δ:1.20-2.30 (6H, m), 2.60-3.40 (4H, m), 4.25-4.45, 5.05-5.25 (1H, m), 6.56-6.65 (1H, m), 6.90-7.05 (1H, m), 7.20-7.60 (5H, m), 7.69 (1H, d, J=6.4 Hz), 8.05-8.25 (2H, m), 9.02 (1H, brs)
40) 1 H-NMR (CDCl3) δ:1.20-2.80 (8H, m), 2.22, 2.26 (6H, s), 3.05- 3.40 (2H, m), 4.25-4.44, 5.10-5.20 (1H, m), 6.50-6.65 (1H, m), 6.90-7.05 (1H, m), 7.20-7.30 (1H, m), 7.30-7.60 (4H, m), 7.71 (1H, d, J=6.3 Hz), 8.15-8.20 (2H, m), 8.73 (1H, s)
41) 1 H-NMR (CDCl3) δ: 1.20-2.80 (6H, m), 2.50 (3H, s), 3.03 (3H, s), 3.10-3.50 (2H, m), 4.20-4.55, 5.10-5.30 (3H, m), 6.65 (1H, d, J=8.4 Hz), 7.03 (1H, d, J=8.4 Hz), 7.20-7.65 (6H, m), 8.09 (1H, s), 8.20-8.25 (2H, m)
42) 1 H-NMR (CDCl3) δ:1.20-2.30 (10H, m), 2.50 (3H, s), 2.30-2.80 (6H, m), 3.10-3.40 (2H, m), 4.20-4.45, 5.05-5.25 (1H, m), 6.50-6.65 (1H, m), 6.90-7.05 (1H,), 7.20-7.60 (6H, m), 8.10-8.20 (2H, m), 8.35 (1H, s)
43) 1 H-NMR (CDCl3) δ: 1.20-2.30 (6H, m), 2.07 (3H, s), 2.50 (3H, s), 2.30-2.80 (6H, m), 3.00-3.70 (6H, m), 4.25-4.45, 5.05-5.25 (1H, m), 6.55-6.65 (1H, m), 6.95-7.05 (1H, m), 7.20-7.65 (6H, m), 8.05-8.30 (3H, m)
44) 1 H-NMR (CDCl3) δ:1.20-2.70 (12H, m), 2.50 (3H, s), 3.00-3.40 (2H, m), 3.65-3.75 (4H, m), 4.30-4.50, 5.10-5.30 (1H, m), 6.55-6.65 (1H, m), 6.95-7.05 (1H, m), 7.25-7.60 (6H, m), 8.11-8.30 (3H, m)
45) 1 H-NMR (CDCl3) δ:0.95-1.05 (6H, m), 1.10-2.90 (9H, m), 2.42 (3H, s), 2.90-3.30 (2H, m), 4.20-4.40, 5.00-5.20 (1H, m), 6.53 (1H, d, J=8.1 Hz), 6.85-7.00 (1H, m), 7.10-7.45 (6H, m), 8.00-8.15 (2H, m), 8.37 (1H, s)
46) 1 H-NMR (CDCl3) δ:1.20-2.70 (6H, m), 2.50 (3H, s), 2.80-3.40 (2H, m), 3.70-3.95 (2H, m), 4.30-4.50, 5.10-5.30 (1H, m), 6.63 (1H, d, J=8.6 Hz), 7.00-7.05 (1H, m), 7.20-7.60 (5H, m), 7.65-7.90 (5H, m), 8.00-8.35 (3H, m)
47) 1 H-NMR (CDCl3) δ: 1.20-2.30 (6H, m), 2.50 (3H, s), 2.55-3.40 (4H, m), 4.25-4.45, 5.10-5.25 (1H, m), 6.50-6.65 (1H, m), 6.95-7.05 (1H, m), 7.20-7.60 (6H, m), 8.05-8.25 (2H, m), 8.47 (1H, s)
48) 1 H-NMR (CDCl3)δ:1.20-2.30 (6H, m), 1.99 (3H, s), 2.50 (3H, s), 2.80-3.60 (4H, m), 4.30-4.50, 5.05-5.25 (1H, m), 5.45-5.80 (1H, m), 6.55-6.65 (1H, m), 6.95-7.05 (1H, m), 7.20-7.60 (6H, m), 8.00-8.30 (3H, m)
49) 1 H-NMR (CDCl3) δ:1.80-2.25 (2H, m), 2.30-3.20 (3H, m), 4.70- 5.20 (1H, m), 5.26 (1H, s), 5.33 (1H, s), 6.61 (1H, d, J=8.4 Hz), 7.01 (1H dd, J=1.9, 8.4 Hz), 7.30-7.60 (5H, m), 7.71 (1H, dd, J=1.7, 6.3 Hz), 8.06 (1H, d, J=1.7 Hz), 8.18 (1H, d, J=8.7 Hz), 8.75 (1H, s)
50) 1 H-NMR (CDCl3) δ:1.50-2.25 (4H, m), 2.70-3.00 (1H, m), 3.40-4.20 (4H, m), 4.70-5.10 (1H, m), 6.54 (1H, d, J=8.3 Hz), 6.99 (1H, dd, J=2.4, 8.3 Hz), 7.25-7.40 (3H, m), 7.55-7.65 (2H, m), 7.84 (1H, d, J=2.4 Hz), 8.10-8.20 (2H, m), 9.07 (1H, s)
51) 1 H-NMR (CDCl3) δ:2.00-2.15 (2H, m), 2.49 (3H, s), 3.13 (2H, s), 3.20 (3H, s), 3.31 (3H, s), 3.10-3.35 (1H, m), 4.70-4.85 (1H, m), 6.58 (1H, d, J=8.4 Hz), 7.00 (1H, dd, J=2.3, 8.3 Hz), 7.20-7.55 (6H, m), 7.95 (1H, d, J=1.8 Hz), 8.20 (1H, d, J=8.7 Hz), 8.55 (1H, s)
52) 1 H-NMR (CDCl3) δ:2.50 (3H, s), 2.65-3.00 (2H, m), 3.40-3.70 (2H, m), 4.00-4.30 (1H, m), 4.65-5.00 (1H, m), 6.73 (1H, d, J=8.4 Hz), 7.11 (1H, dd, J=2.4, 8.4 Hz), 7.20-7.65 (6H, m), 8.07 (1H, d, J=1.7 Hz), 8.24 (1H, d, J=8.7 Hz), 8.50 (1H, s)
53) 1 H-NMR (CDCl3) δ:1.80-2.30 (2H, m), 2.49 (3H, s), 2.75-3.40 (3H, m), 3.75-4.00, 4.30-4.45 (1H, m), 4.70-5.10 (1H, m), 6.55-6.65 (1H, m), 7.01 (1H, d, J=8.3 Hz), 7.20-7.60 (6H, m), 8.01 (1H, s), 8.20 (1H, d, J=8.6 Hz), 8.50 (1H, s)
54) 1 H-NMR (CDCl3) δ:1.55-2.50 (4H, m), 2.51 (3H, s), 2.65-3.00 (1H, m), 4.00-4.25 (2H, m), 4.45-4.80 (2H, m), 5.00-5.45 (2H, m), 5.75-6.15 (1H, m), 6.61 (1H, d, J=8.1 Hz), 7.03 (1H, d, J=8.2 Hz), 7.20-7.80 (6H, m), 8.05-8.40 (3H, m)
55) 1 H-NMR (CDCl3) δ:0.35-0.65 (4H, m), 1.35-2.40 (6H, m), 2.50 (3H, s), 2.60-3.30 (1H, m), 3.90-5.20 (2H, m), 6.62 (1H, d, J=8.2 Hz), 6.95-7.10 (1H, m), 7.20-7.85 (6H, m), 8.15-8.40 (3H, m)
56) 1 H-NMR (CDCl3) δ:1.25-2.20 (4H, m), 2.40-3.00 (5H, m), 3.10-3.35 (1H, m), 3.50-3.90 (1H, m), 4.40-4.55, 5.00-5.15 (1H, m), 5.90-6.10 (1H, m), 6.59 (1H, d, J=8.3 Hz), 6.98 (1H, d, J=8.3 Hz), 7.12 (1H, d, J=2.1 Hz), 7.30-7.60 (3H, m), 7.60-7.75 (2H, m), 8.10-8.30 (2H, m), 8.94 (1H, s)
EXAMPLE 149
To a suspension of 7-chloro-5-hydroxy-1-[6-(2-methoxycarbonyl-benzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) in methanol (4 ml) is added 5% aqueous sodium hydroxide solution (1.5 ml), and the mixture is stirred at room temperature for one hour. To the reaction solution are added water and diluted aqueous hydrochloric acid solution in order to make the mixture weak acidic. The mixture is extracted with dichloromethane, and the extract is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to remove the solvent. The residue is recrystallized from dichloromethane-methanol to give 7-chloro-5-hydroxy-1-[6-(2-carboxybenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (150 mg) as white powder.
M.p. 153°-155° C.
Using the suitable starting compounds, there are obtained the compounds of Examples 83, 85 and 86 in the same manner as in Example 149.
EXAMPLE 150
To a solution of 7-chloro-1-{6-[2-(3-ethoxycarbonylpropoxy)benzoyl-amino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.5 g)in ethylene glycol dimethyl ether (70 ml)is added sodium trimethoxyborohydride (3.78 g), and the mixture is refluxed for 3 hours. The reaction solution is gradually poured into diluted hydrochloric acid, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-1-{6-[2-(4-hydroxybutoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (1.12 g) as white powder.
M.p. 157°-158.5° C.
Using the suitable starting compounds, there is obtained the compound of Example 83 in the same manner as in Example 150.
EXAMPLE 151
To a solution of 7-chloro-1-[6-(2-carboxymethoxybenzoylamino)-nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) in dichloromethane (10 ml) is added with stirring N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.25 g) under ice-cooling, and the mixture is stirred at room temperature for 15 minutes. Subsequently, to the reaction mixture is added N-methylpiperazine (0.11 ml), and thereto is added triethylamine (0.23 ml). The mixture is stirred at room temperature overnight, and thereto is added water. The mixture is extracted with dichloromethane, and the extract is washed successively with diluted aqueous sodium hydroxide solution and water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-1-{6-[2-(4-methyl-1-piperazinyl)-carbonyl methoxybenzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (390 mg) as white powder.
M.p. 111°-114° C.
Using the suitable starting compounds, there are obtained the compounds of Examples 89 and 97 in the same manner as in Example 151.
EXAMPLE 152
To a solution of 7-chloro-1-{6-[2-(2-hydroxyethoxy)benzoylamino]-nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g )in pyridine (10 ml) is added with stirring methanesulfonyl chloride (0.1 ml) under ice-cooling, and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added water, and the precipitated crystals are collected by filtration, and dissolved in dichloromethane. The mixture is washed successively with diluted hydrochloric acid and water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is crystallized from diethyl ether to give 7-chloro-1-{6-[2-(2-methanesulfonyloxyethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.59 g) as white powder.
1 H-NMR (CDCl3) δ:1.40-1.70 (1H, m), 1.85-2.20 (3H, m), 2.70- 3.15 (3H, m), 3.06 (3H, s), 4.45-4.55 (2H, m), 4.60-4.70 (2H, m), 4.95-5.15 (1H, m), 6.62 (1H, d, J=8.2 Hz), 6.97 (2H, t, J=8.2 Hz), 7.17 (1H, t, J=7.2 Hz), 7.28 (1H, s), 7.45-7.60 (2H, m), 8.09 (1H, s), 8.15-8.30 (2H, m), 10.23 (1H,s)
EXAMPLE 153
To a solution of 7-chloro-1-{6-[2-(2-methanesulfonyloxyethoxy)-benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dimethylformamide (5 ml) are added sodium iodide (0.22 g), potassium carbonate (0.23 g) and 4-acetylaminopiperidine (0.2 g), and the mixture is heated with stirring at 110° C. for 2 hours. The mixture is cooled, and thereto is added water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-1-{6-[2-(4-acetylamino-1-piperidinyl)-ethoxy]benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) as white powder.
M.p. 159°-162° C.
Using the suitable starting compounds, there are obtained the compounds of Examples 91, 93, 95 and 96 in the same manner as in Example 153.
EXAMPLE 154
To a solution of 7-chloro-1-{6-[2-(2-methanesulfonyloxyethoxy)-benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.75 g) in dimethylformamide (10 ml) is added potassium phthalimide (0.26 g), and the mixture is stirred at 110° C. for one hour. The mixture is poured into ice-water, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is purified by silica gel column chromatography to give 7-chloro-1-[6-(6,7-benzo-1-oxo-4-azepin-5-on-4-yl)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g, Compound A) and 7-chloro-1-{6-[2-(2-phthalimido-ethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g, Compound B), separately.
Compound A
White powder
M.p. 176°-179° C. (recrystallized from ethyl acetate)
Compound B
White powder
1 H-NMR (CDCl3) δ:1.30-1.65 (1H, m), 1.90-2.20 (3H, m), 2.60-3.10 (3H, m), 4.10-4.30 (2H, m), 4.40-4.60 (2H, m), 4.90-5.10 (1H, m), 6.60 (1H, d, J=8 Hz), 6.90-7.00 (2H, m), 7.00-7.15 (2H, m), 7.25-7.30 (1H, m), 7.40-7.55 (2H, m), 7.60-7.85 (4H, m), 7.97 (1H, s), 8.10-8.20 (2H, m), 10.05 (1H, s)
EXAMPLE 155
To a solution of 7-chloro-1-{6-[2-(2-phthalimidoethoxy)benzoyl-amino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g)in ethanol (5 ml) is added hydrazine monohydrate (0.03 ml), and the mixture is refluxed for one hour, and cooled. To the mixture is added water, and the mixture is made acidic with diluted hydrochloric acid, and washed with diethyl ether. The aqueous layer is made basic with aqueous sodium hydroxide solution, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is crystallized from diethyl ether to give 7-chloro-1-{6-[2-(2-aminoethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (110 mg) as white powder.
1 H-NMR (CDCl3) δ:1.35-2.20 (4H, m), 2.60-3.40 (5H, m), 4.15-4.30 (2H, m), 4.90-5.10 (1H, m), 6.61 (1H, d, J=8.2 Hz), 6.90-7.30 (4H, m), 7.40-7.55 (2H, m), 8.15-8.25 (3H, m), 10.81 (1H, s)
EXAMPLE 156
To a solution of 7-chloro-1-{6-[2-(2-aminoethoxy)benzoylamino]-nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.11 g) in methanol (3 ml) is added 37% formalin (0.24 ml), and thereto is added sodium cyanoborohydride (0.044 g), and thereto is added with stirring acetic acid (0.18 ml) at 10° C. The mixture is stirred at room temperature for one hour, and poured into ice-water, and the mixture is made basic with potassium carbonate, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and the resultant is dissolved in ethanol (5 ml), and thereto is added conc. hydrochloric acid, and the mixture is stirred at room temperature for one hour. The mixture is evaporated under reduced pressure to remove the solvent, and crystallized from diethyl ether to give 7-chloro-1-{6-[2-(2-dimethylaminoethoxy)benzoyl-amino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine dihydrochloride (53 mg) as white powder.
1 H-NMR (DMSO-d6) δ:1.30-1.60 (1H, m), 1.80-2.15 (3H, m), 2.79 (6H, s), 2.60-3.20 (3H, m), 3.55 (2H, s), 4.53 (2H, s), 4.75-4.90 (1H, m), 5.60 (1H, brs), 6.87 (1H, d, J=8.4 Hz), 7.05-7.25 (3H, m), 7.45-7.75 (4H, m), 8.05-8.15 (2H, m), 10.69 (1H, s), 10.90 (1H, brs)
Using the suitable starting compounds, there is obtained the compound of Example 91 in the same manner as in Example 156.
EXAMPLE 157
To a solution of 7-chloro-5-(4-t-butoxycarbonyl-1-piperazinyl)-carbonylmethyl-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.2 g)in dioxane (20 ml)is added 5 N hydrochloric acid (2 ml), and the mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the mixture is made basic with aqueous sodium hydroxide solution, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from ethyl acetate-diethyl ether to give 7-chloro-5-(1-piperazinyl)carboxymethyl-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.54 g) as white powder.
M.p. 157°-160° C.
EXAMPLE 158
To a solution of 7-chloro-5-methoxycarbonylmethyl-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (8 g) in ethylene glycol dimethyl ether (50 ml)is added sodium trimethoxyborohydride (6 g), and the mixture is refluxed for 4 hours. To the mixture is added sodium trimethoxyborohydride (3 g), and the mixture is refluxed for two hours. The reaction solution is gradually poured into diluted aqueous hydrochloric acid solution, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-(2-hydroxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-l H-benzazepine (3.1 g) as white powder.
M.p. 161°-163° C.
Using the suitable starting compounds, there is obtained the compound of Example 123 in the same manner as in Example 158.
EXAMPLE 159
To a solution of 7-chloro-5-(2-hydroxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) in pyridine (6 ml) is added acetic anhydride (0.09 ml), and the mixture is stirred at 80° C. for 2 hours. The reaction solution is poured into water, and extracted with ethyl acetate. The extract is washed successively with diluted hydrochloric acid, water and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-(2-acetyloxyethyl)-1-[6-(2-chlorobenzoylamino )nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (230 mg) as white powder.
M.p. 151°-153° C.
Using the suitable starting compounds, there is obtained the compound of Example 124 in the same manner as in Example 159.
EXAMPLE 160
To a solution of 7-chloro-5-(2-hydroxyethyl)-1-[6-(2-chlorobenzoyl-amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (3.7 g) in pyridine (50 ml) is added with stirring methanesulfonyl chloride (0.71 ml) under ice-cooling, and the mixture is stirred at room temperature for 3 hours. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The extract is washed with successively with diluted hydrochloric acid and water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-methanesulfonyloxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.8 g) as colorless amorphous.
1 H-NMR (CDCl3) δ:1.30-2.50 (6H, m), 2.55-3.45 (2H, m), 3.04 (3H, s), 4.20-4.60, 5.10-5.25 (3H, m), 6.64 (1H, d, J=8.3 Hz), 7.03 (1H, d, J=8.2 Hz), 7.15-7.50 (5H, m), 7.56 (1H, d, J=8.6 Hz), 7.72 (1H, d, J=6.2 Hz), 8.09 (1H, s), 8.21 (1H, d, J=8.7 Hz), 8.74 (1H, s)
Using the suitable starting compounds, there is obtained the compound of Example 134 in the same manner as Example 160.
EXAMPLE 161
To a solution of 7-chloro-5-(2-methanesulfonyloxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) in dimethylformamide (5 ml) are added pyrrolidine (0.09 ml), sodium iodide (0.14 g) and potassium carbonate (0.15 g), and the mixture is stirred at 110° C. for 2 hours. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-[2-(1-pyrrolidinyl)ethyl]-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (98 mg) as colorless amorphous.
1 H-NMR (CDCl3) δ: 1.30-2.80 (14H, m), 3.05-3.40 (2H, m), 4.25-4.45, 5.05-5.25 (1H, m), 6.60 (1H, d, J=8.2 Hz), 6.90-7.05 (1H, m), 7.25-7.60 (5H, m), 7.72 (1H, d, J=6.4 Hz), 8.17 (1H, d, J=8.1 Hz), 8.70 (1H, s)
Using the suitable starting compounds, there are obtained the compounds of Examples 127-133 and 135-143 in the same manner as in Example 161.
EXAMPLE 162
To a solution of 7-chloro-5-(2-methanesulfonyloxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.6 g) in dimethylformamide (30 ml) is added potassium phthalimide (0.58 g), and the mixture is stirred at 110° C. for 3 hours. The mixture is poured into ice-water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-phthalimidoethyl)-1-[6-(2-chlorobenzoyl-amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.8 g) as colorless amorphous.
1 H-NMR (CDCl3) δ: 1.25-2.50 (6H, m), 2.60-3.40 (2H, m), 3.70-4.00 (2H, m), 4.30-4.50, 5.10-5.30 (1H, m), 6.62 (1H, d, J=8.5 Hz), 6.90-7.15 (1H, m), 7.25-7.60 (5H, m), 7.65-7.90 (5H, m), 8.00-8.30 (2H, m), 8.72 (1H, s)
Using the suitable starting compounds, there is obtained the compound of Example 141 in the same manner as in Example 162.
EXAMPLE 163
To a solution of 7-chloro-5-(2-phthalimidoethyl)-1-[6-(2-chloro-benzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.8 g) in ethanol (50 ml) is added hydrazine monohydrate (0.19 ml), and the mixture is refluxed for 4 hours. The mixture is cooled, and thereto is added water. The mixture is extracted with dichloromethane, and the extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-aminoethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g) as colorless amorphous.
1 H-NMR (CDCl3) δ: 1.20-2.30 (6H, m), 2.60-3.40 (4H, m), 4.25-4.45, 5.05-5.25 (1H, m), 6.56-6.65 (1H,m), 6.90-7.05 (1H, m), 7.20-7.60 (5H, m), 7.69 (1H, d, J=6.4 Hz), 8.05-8.25 (2H, m), 9.02 (1H, brs)
Using the suitable starting compounds, there is obtained the compound of Example 142 in the same manner as in Example 163.
EXAMPLE 164
To a solution of 7-chloro-5-(2-aminoethyl)-1-[6-(2-chlorobenzoyl-amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g) in methanol (20 ml) is added 37% formalin (1.4 ml), and thereto is added sodium cyanoborohydride (0.2 g), and further thereto is added with stirring acetic acid (0.9 ml) at 10° C., and the mixture is stirred at room temperature for 3 hours. The mixture is poured into ice-water, and the mixture is made basic with potassium carbonate, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-dimethylaminoethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.37 g) as colorless amorphous.
1 H-NMR (CDCl3) δ:1.20-2.80 (8H, m), 2.22, 2.26 (6H, s), 3.05-3.40 (2H, m), 4.25-4.44, 5.10-5.20 (1H, m), 6.50-6.65 (1H, m), 6.90-7.05 (1H, m), 7.20-7.30 (1H, m), 7.30-7.60 (4H, m), 7.71 (1H, d, J=6.3 Hz), 8.15-8.20 (2H, m), 8.73 (1H, s)
Using the suitable starting compounds, there are obtained the compounds of Examples 130 and 139 in the same manner as in Example 164.
EXAMPLE 165
To a solution of 7-chloro-5-(2-aminoethyl)-1-[6-(2-methylbenzoyl-amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.42 g) in pyridine (10 ml) is added acetic anhydride (0.13 ml), and the mixture is stirred at 80° C. for 2 hours, and then stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed successively with diluted hydrochloric acid, water, and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-acetylamino-ethyl)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (91 mg) as white powder.
1 H-NMR (CDCl3) δ:1.20-2.30 (6H, m), 1.99 (3H, s), 2.50 (3H, s), 2.80-3.60 (4H, m), 4.30-4.50,5.05-5.25 (1H, m), 5,45-5.80 (1H, m), 6.55-6.65 (1H, m), 6.95-7.05 (1H, m), 7.20-7.60 (6H, m), 8.00-8.30 (3H, m)
EXAMPLE 166
To a solution of 7-chloro-4,4-dimethoxy-1-[6-(2-methylbenzoyl-amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1 g) in acetone (10 ml) is added 1N hydrochloric acid (5 ml), and the mixture is stirred at room temperature for 6 hours. Water is added to the reaction solution, and the mixture is neutralized with aqueous sodium hydroxide solution, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-4-oxo-1-[6-(2-methylbenzoylamino )nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.92 g) as colorless amorphous.
1 H-NMR (CDCl3) δ:2.50 (3H, s), 2.65-3.00 (2H, m), 3.40-3.70 (2H, m), 4.00-4.30 (1H, m), 4.65-5.00 (1H, m), 6.73 (1H, d, J=8.4 Hz), 7.11 (1H, dd, J=2.4, 8.4 Hz), 7.20-7.65 (6H, m), 8.07 (1H, d, J=1.7 Hz), 8.24 (1H, d, J=8.7 Hz), 8.50 (1H, s)
EXAMPLE 167-198
Using the suitable starting compounds, the following compounds listed in Table 3 are obtained in the same manner as in Examples 1 and 17. Table 4 shows the NMR analysis of these compounds.
              TABLE 3                                                     
______________________________________                                    
 ##STR315##                                                               
______________________________________                                    
Example 167                                                               
Structure:                                                                
 ##STR316##                                                               
 ##STR317##                                                               
R.sup.3 : H                                                               
 ##STR318##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 57)                                                         
Form: Free                                                                
Example 168                                                               
Structure:                                                                
 ##STR319##                                                               
R.sup.2 : OCH.sub.2 COOH (5-position)                                     
R.sup.3 : H                                                               
 ##STR320##                                                               
Crystalline Form: White powder                                            
Recrystallization solvent: Diethyl ether-dichloromethane                  
Melting point: 220-222° C.                                         
Form: Free                                                                
Example 169                                                               
Structure:                                                                
 ##STR321##                                                               
R.sup.2 : OCH.sub.2 COOH (5-position)                                     
R.sup.3 : H                                                               
 ##STR322##                                                               
Crystalline Form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 223-225° C.                                         
Form: Free                                                                
Example 170                                                               
Structure:                                                                
 ##STR323##                                                               
R.sup.2 : OCH.sub.2 CONH.sub.2 (5-position)                               
R.sup.3 : H                                                               
 ##STR324##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 58)                                                         
Form: Free                                                                
Example 171                                                               
Structure:                                                                
 ##STR325##                                                               
R.sup.2 : OCH.sub.2 CONH.sub.2 (5-position)                               
R.sup.3 : H                                                               
 ##STR326##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 59)                                                         
Form: Free                                                                
Example 172                                                               
Structure:                                                                
 ##STR327##                                                               
R.sup.2 : OCH.sub.2 CON(CH.sub.3).sub.2 (5-position)                      
R.sup.3 : H                                                               
 ##STR328##                                                               
Crystalline Form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 107-110° C.                                         
Form: Free                                                                
Example 173                                                               
Structure:                                                                
 ##STR329##                                                               
R.sup.2 : OCH.sub.2 CON(CH.sub.3).sub.2 (5-position)                      
R.sup.3 : H                                                               
 ##STR330##                                                               
Crystalline Form: White powder                                            
Recrystallization solvent: Dichloromethane-diethyl ether                  
Melting point: 119-122° C.                                         
Form: Free                                                                
Example 174                                                               
Structure:                                                                
 ##STR331##                                                               
 ##STR332##                                                               
R.sup.3 : H                                                               
 ##STR333##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 60)                                                         
Form: Free                                                                
Example 175                                                               
Structure:                                                                
 ##STR334##                                                               
 ##STR335##                                                               
R.sup.3 : H                                                               
 ##STR336##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 61)                                                         
Form: Free                                                                
Example 176                                                               
Structure:                                                                
 ##STR337##                                                               
R.sup.2 : O(CH.sub.2).sub.2 OH (5-position)                               
R.sup.3 : H                                                               
 ##STR338##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 62)                                                         
Form: Free                                                                
Example 177                                                               
Structure:                                                                
 ##STR339##                                                               
R.sup.2 : O(CH.sub.2).sub.2 N(CH.sub.3).sub.2 (5-position)                
R.sup.3 : H                                                               
 ##STR340##                                                               
Example 178                                                               
Structure:                                                                
 ##STR341##                                                               
 ##STR342##                                                               
R.sup.3 : H                                                               
 ##STR343##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 63)                                                         
Form: Free                                                                
Example 179                                                               
Structure:                                                                
 ##STR344##                                                               
 ##STR345##                                                               
R.sup.3 : H                                                               
 ##STR346##                                                               
Example 180                                                               
Structure:                                                                
 ##STR347##                                                               
 ##STR348##                                                               
R.sup.3 : H                                                               
 ##STR349##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 64)                                                         
Form: Free                                                                
Example 181                                                               
Structure:                                                                
 ##STR350##                                                               
 ##STR351##                                                               
R.sup.3 : H                                                               
 ##STR352##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 65)                                                         
Form: Free                                                                
Example 182                                                               
Structure:                                                                
 ##STR353##                                                               
 ##STR354##                                                               
R.sup.3 : H                                                               
 ##STR355##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 66)                                                         
Form: Free                                                                
Example 183                                                               
Structure:                                                                
 ##STR356##                                                               
 ##STR357##                                                               
R.sup.3 : H                                                               
 ##STR358##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 67)                                                         
Form: Free                                                                
Example 184                                                               
Structure:                                                                
 ##STR359##                                                               
 ##STR360##                                                               
R.sup.3 : H                                                               
 ##STR361##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 68)                                                         
Form: Free                                                                
Example 185                                                               
Structure:                                                                
 ##STR362##                                                               
 ##STR363##                                                               
R.sup.3 : H                                                               
 ##STR364##                                                               
Crystalline Form: Yellow amorphous                                        
NMR analysis: 69)                                                         
Form: Free                                                                
Example 186                                                               
Structure:                                                                
 ##STR365##                                                               
 ##STR366##                                                               
R.sup.3 : H                                                               
 ##STR367##                                                               
Crystalline Form: Brown amorphous                                         
NMR analysis: 70)                                                         
Form: Free                                                                
Example 187                                                               
Structure:                                                                
 ##STR368##                                                               
 ##STR369##                                                               
R.sup.3 : H                                                               
 ##STR370##                                                               
Crystalline Form: Brown amorphous                                         
NMR analysis: 71)                                                         
Form: Free                                                                
Example 188                                                               
Structure:                                                                
 ##STR371##                                                               
R.sup.2 : O(CH.sub.2).sub.2 NHCOCH.sub.3 (5-position)                     
R.sup.3 : H                                                               
 ##STR372##                                                               
Example 189                                                               
Structure:                                                                
 ##STR373##                                                               
R.sup.2 : OCOCH.sub.2 N(CH.sub.3).sub.2 (5-position)                      
R.sup.3 : H                                                               
 ##STR374##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 72)                                                         
Form: 2 HCl                                                               
Example 190                                                               
Structure:                                                                
 ##STR375##                                                               
R.sup.2 : OCOCH.sub.2 N(CH.sub.3).sub.2 (5-position)                      
R.sup.3 : H                                                               
 ##STR376##                                                               
Crystalline Form: Colorless amorphous                                     
NMR analysis: 73)                                                         
Form: Free                                                                
Example 191                                                               
Structure:                                                                
 ##STR377##                                                               
R.sup.2 : OH (5-position)                                                 
R.sup.3 : H                                                               
 ##STR378##                                                               
Crystalline Form: White powder                                            
Recrystallization solvent: Diethyl ether                                  
Melting point: 115-118° C.                                         
Form: Free                                                                
Example 192                                                               
Structure:                                                                
 ##STR379##                                                               
R.sup.2 : N(CH.sub.3).sub.2 (5-position)                                  
R.sup.3 : H                                                               
 ##STR380##                                                               
Crystalline Form: Colorless oil                                           
NMR analysis: 74)                                                         
Form: Free                                                                
Example 193                                                               
Structure:                                                                
 ##STR381##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR382##                                                               
Example 194                                                               
Structure:                                                                
 ##STR383##                                                               
R.sup.2 : H                                                               
R.sup.3 : H                                                               
 ##STR384##                                                               
Example 195                                                               
Structure:                                                                
 ##STR385##                                                               
 ##STR386##                                                               
R.sup.3 : H                                                               
 ##STR387##                                                               
Example 196                                                               
Structure:                                                                
 ##STR388##                                                               
 ##STR389##                                                               
R.sup.3 : H                                                               
 ##STR390##                                                               
Example 197                                                               
Structure:                                                                
 ##STR391##                                                               
 ##STR392##                                                               
R.sup.3 : H                                                               
 ##STR393##                                                               
Example 198                                                               
Structure:                                                                
 ##STR394##                                                               
 ##STR395##                                                               
R.sup.3 : H                                                               
 ##STR396##                                                               
______________________________________
TABLE 4
57) 1 H-NMR (CDCl3) δ:1.60-1.90 (2H, m), 2.30-2.65 (9H, m), 2.70-3.05 (1H, m), 3.45-3.80 (4H, m), 4.20-5.20 (4H, m), 6.55-6.70 (1H, m), 7.00-7.15 (1H, m), 7.30-7.50 (3H, m), 7.50-7.85 (3H, m), 8.20-8.30 (2H, m), 8.86 (1H, s)
58) 1 H-NMR (CDCl3) 821.60-2.60 (4H, m), 2.50 (3H, s), 2.70-3.05 (1H, m), 4.00-4.20 (2H, m), 4.50-5.15 (2H, m), 5.70-6280 (2H, m), 6.60-6.80 (1H, m), 7.00-7.75 (7H, m), 8.00-8.30 (2H, m), 8.53 (1H, s)
59) 1 H-NMR (CDCl3) δ:1.60-2.55 (4H, m), 2.70-3.05 (1H, m), 3.90-4.25 (2H, m), 4.50-5.15 (2H, m), 5.85-6.80 (2H, m), 6.55-6.80 (1H, m), 7.00-7.20 (1H, m), 7.25-7.55 (4H, m), 7.55-7.75 (2H, m), 8.00-8.30 (2H, m), 8.99 (1H, s)
60) 1 H-NMR (CDCl3) δ:0.85-1.15 (6H, m), 1.55-1.90 (2H, m), 2.25-2.70 (11H, m), 2.70-3.15 (4H, m), 3.20-3.65 (2H, m), 4.15-5.20 (4H, m), 6.55-6.70 (1H, m), 7.00-7.15 (1H, m), 7.20-7.85 (6H, m), 8.05-8.35 (2H, m), 8.35-8.50 (1H, m)
61 ) 1 H-NMR (CDCl3) δ:0.85-1.15 (6H, m), 1.55-1.90 (2H, m), 2.30-2.70 (8H, m), 2.70-3.15(4H, m), 3.20-3.65 (2H, m), 4.15-5.20 (4H, m), 6.55-6.75 (1H, m), 6.95-7.15(1H, m), 7.30-7.55 (3H, m), 7.55-7.85 (3H, m), 8.10-8.35 (2H, m), 8.75-8.95(1H, m)
62) 1 H-NMR (CDCl3) 8 : 1.50-2.55 (4H, m), 2.70-3.00 (1H, m), 3.50-4.00 (4H, m), 4.50-5.10 (2H, m), 6.61 (1H, d, J=8.1 Hz), 7.00-7.15 (1H, m), 7.25-7.85 (6H, m), 8.05-8.35 (2H, m), 8.85 (1H, s)
63) 1 H-NMR (CDCl3) δ:1.50-2.60 (4H, m), 2.51 (3H, s), 2.65-3.05 (1H, m), 3.70-4.05 (2H, m), 4.05-5.20 (4H, m), 6.55-6.70 (1H, m), 6.90-7.80 (10H, m), 8.05-8.25 (2H, m), 8.52, 8.61 (1H, s)
64) 1 H-NMR (CDCl3) δ:1.60-1.90 (2H, m), 2.01,2.06 (3H, s), 1.90-3.00 (9H, m), 2.50 (3H, s), 3.30-3.85 (6H, m), 4.45-5.15 (2H, m), 6.62 (1H, d, J=8.3 Hz), 7.04 (1H, d, J=8.2 Hz), 7.20-7.85 (6H, m), 8.05-8.35 (2H, m), 8.52, 8.57 (1H, s)
65) 1 H-NMR (CDCl3) δ:1.55-3.00 (11H, m), 2.02, 2.10 (3H, s), 3.30-3.85 (6H, m), 4.40-5.15 (2H, m), 6.62 (1H, d, J=8.1 Hz), 7.04 (1H, d, J=8.3 Hz), 7.35-7.90 (6H, m), 8.10-8.40 (2H, m), 8.76, 8.80 (1H, s)
66) 1 H-NMR (CDCl3) δ:1.55-3.00 (11H, m), 2.50 (3H, s), 3.55-3.90 (6H, m), 4.45-5.15 (2H, m), 6.61 (1H, d, J=8.2 Hz), 7.03 (1H, d, J=8.2 Hz), 7.20-7.85 (6H, m), 8.05-8.35 (2H, m), 8.51 (1H, s)
67) 1 H-NMR (CDCl3) δ:1.55-3.00 (11H, m), 3.55-3.90 (6H, m), 4.45-5.15 (2H, m), 6.61(1H, d, J=8.3 Hz), 7.03 (1H, d, J=8.2 Hz), 7.30-7.85 (6H, m), 8.10-8.35 (2H, m), 8.75, 8.80 (1H, s)
68) 1 H-NMR (CDCl3) δ:0.20-0.60 (4H, m), 1.55-2.65 (5H, m), 2.50 (3H, s), 2.65-3.10 (3H, m), 3.50-3.85 (2H, m), 4.40-5.15 (2H, m), 6.62 (1H, d, J=8.2 Hz), 7.04 (1H, d, J=8.1 Hz), 7.20-7.80 (6H, m), 8.09-8.40 (3H, m)
69) 1 H-NMR (CDCl3) 8: 0.20-0.60 (4H, m), 1.50-2.60 (5H, m), 2.65-3.10 (3H, m), 3.50-3.80 (2H, m), 4.45-5.15 (2H, m), 6.61 (1H, d, J=8.4 Hz), 7.04 (1H, d, J=6.9 Hz), 7.30-7.85 (6H, m), 8.05-8.35 (2H, m), 8.78 (1H
70) 1 H-NMR (CDCl3) δ:1.05-2.20 (12H, m), 2.20-2.60 (1H, m), 2.50 (3H, s), 2.70-3.05 (3H, m), 3.50-3.90 (2H, m), 4.45-5.15 (2H, m), 6.55-6.70 (1H, m), 7.04 (1H, d, J=8.4 Hz),7.20-7.80 (6H, m), 8.05-8.30 (2H, m), 8.35-8.50 (1H, m)
71) 1 H-NMR (CDCl3) δ: 1.05-2.60 (12H, m), 2.65-3.30 (4H,), 2.50-3.85 (2H, m), 4.45-5.10 (2H, m), 6.55-6.70 (1H, m), 7.04 (1H, d, J=8.0 Hz), 7.30-7.80 (6H, m), 8.10-8.33 (2H, m), 8.60-8.90 (1H, m)
72) 1 H-NMR (CDCl3) δ:1.60-2.45 (4H, m), 2.30-2.40 (3H, m), 2.70-3.10 (7H, m), 4.10-5.00 (3H, m), 6.05-6.20 (1H, m), 6.95 (1H, d, J=8.2 Hz), 7.15-7.60 (6H, m), 7.70-7.90 (1H, m), 8.03 (1H, d, J=8.6 Hz), 8.20 (1H, s), 11.04 (1H, s), 11.28, 11.85 (1H, s)
73) 1 H-NMR (CDCl3) 8:2.34, 2.43 (6H, s), 1.70-2.65 (5H, m), 2.70-3.00 (1H, m), 3.40 (2H, s), 4.70-5.15 (1H, m), 6.00-6.20 (1H, m), 6.55-6.70 (1H, m), 7.00-7.15 (1H, m), 7.30-7.45 (3H, m), 7.50-7.70 (2H, m), 8.05-8.25 (2H, m), 9.15-9.50 (1H, br)
74) 1 H-NMR (CDCl3) 8: 1.16-2.57 (4H, m), 2.15, 2.40 (total, 6H, s), 2.61-3.63 (2H, m), 4.03-5.09 (1H, m), 6.53-8.26 (10H, m), 8.36, 8.77 (total, 1H, brs)
Pharmacological Test Experiment 1: V1 receptor binding assay
Using rat liver plasma membrane preparations prepared according to Ichihara's method [cf: Akira Ichihara, J. Bio. Chem., 258, 9283 (1983)], the plasma membrane (50000 dpm, 2×10-10 M) of [3 H]-Arg-vasopressin and a test compound (60 μg, 10-8 to 10-4 M) are incubated at 37° C. for 10 minutes in 100 mM Tris-HCl buffer (pH: 8.0) (250 μl) containing 5 mM MgCl2, 1 mM EDTA and 0.1% BSA. After incubation, the mixture is filtered three times using the glass filter (GF/F) so as to separate the membrane preparation binding with vasopressin and then washed with the buffer (5 ml). This glass filter is taken out and mixed with liquid scintillation cocktail. The amount of [3 H]-vasopressin binding with the membrane is measured by liquid scintillation counter and the rate of the inhibitory effect of the test compound is estimated according to the following equation. ##EQU1## C1 : The amount of [3 H]-vasopressin binding with the membrane in the presence of the test compound (known amount)
C0 : The amount of [3 H]-vasopressin binding with the membrane in the absence of the test compound
B1 : The amount of [3 H]-vasopressin binding with the membrane in the presence of the excess amount of vasopressin (10-6 M)
The results are expressed as IC50 value, which is the concentration of the test compound required to achieve the inhibitory effect in the rate of 50%.
The results are shown in the following Table 5.
Experiment 2: V2 receptor binding assay
Using rat kidney plasma membrane preparations prepared according to O. Hechter's method [cf: J. Bio. Chem., 253, 3211 (1978)], the plasma membrane (100000 dpm, 4×10-10 M) of [3 H]-Arg-vasopressin and a test compound (0.6 mg, 10-10 to 10-5 M) are incubated at 4° C. for 3 hours in 100 mM Tris-HCl buffer (pH: 8.0) (250 μl) containing 5 mM MgCl2, 1 mM EDTA and 0.1% BSA. After incubation, the mixture is filtered using the glass filter (GF/F) so as to separate the membrane preparation binding with vasopressin and then washed twice with the buffer (each 5 ml). This glass filter is taken out and mixed with liquid scintillation cocktail. The amount of [3 H]-vasopressin binding with the membrane is measured by liquid scintillation counter and the rate of the inhibitory effect of the test compound is estimated according to the following equation. ##EQU2## C1 : The amount of [3 H]-vasopressin binding with the membrane in the presence of the test compound (known amount)
C0 : The amount of [3 H]-vasopressin binding with the membrane in the absence of the test compound
B1 : The amount of [3 H]-vasopressin binding with the membrane in the presence of the excess amount of vasopressin (10-6 M)
The results are expressed as IC50 value, which is the concentration of the test compound required to achieve the inhibitory effect in the rate of 50%.
The results are shown in the following Table 5.
              TABLE 5                                                     
______________________________________                                    
              IC.sub.50 (μM)                                           
                           IC.sub.50 (μM)                              
              in V1 receptor                                              
                           in V2 receptor                                 
Test compound No                                                          
              binding assay                                               
                           binding assay                                  
______________________________________                                    
Compound of Ex. 25                                                        
              0.014        0.004                                          
Compound of Ex. 26                                                        
              0.078        0.021                                          
Compound of Ex. 28                                                        
              0.077        0.17                                           
Compound of Ex. 29                                                        
              0.024        0.011                                          
Compound of Ex. 31                                                        
              0.057        0.12                                           
Compound of Ex. 32                                                        
              0.012        0.016                                          
Compound of Ex. 33                                                        
              0.007        0.003                                          
Compound of Ex. 34                                                        
              0.066        0.016                                          
Compound of Ex. 35                                                        
              0.020        0.007                                          
Compound of Ex. 36                                                        
              0.043        0.003                                          
Compound of Ex. 37                                                        
              0.011        0.005                                          
Compound of Ex. 38                                                        
              0.026        0.003                                          
Compound of Ex. 39                                                        
              0.91         0.068                                          
Compound of Ex. 40                                                        
              0.044        0.009                                          
Compound of Ex. 41                                                        
              0.022        0.004                                          
Compound of Ex. 42                                                        
              0.030        0.003                                          
Compound of Ex. 43                                                        
              0.013        0.010                                          
Compound of Ex. 44                                                        
              0.008        0.011                                          
Compound of Ex. 45                                                        
              0.005        0.007                                          
Compound of Ex. 47                                                        
              0.15         0.089                                          
Compound of Ex. 48                                                        
              0.067        0.30                                           
Compound of Ex. 49                                                        
              0.041        0.25                                           
Compound of Ex. 50                                                        
              0.078        0.061                                          
Compound of Ex. 52                                                        
              0.051        0.022                                          
Compound of Ex. 53                                                        
              0.055        0.019                                          
Compound of Ex. 73                                                        
              0.012        0.0019                                         
Compound of Ex. 76                                                        
              0.027        0.008                                          
Compound of Ex. 78                                                        
              0.017        0.010                                          
Compound of Ex. 79                                                        
              0.041        0.0037                                         
Compound of Ex. 83                                                        
              0.071        0.43                                           
Compound of Ex. 88                                                        
              0.026        0.20                                           
Compound of Ex. 92                                                        
              0.060        0.38                                           
Compound of Ex. 94                                                        
              0.042        0.036                                          
Compound of Ex. 96                                                        
              0.043        0.30                                           
Compound of Ex. 97                                                        
              0.005        0.16                                           
Compound of Ex. 101                                                       
              0.49         0.033                                          
Compound of Ex. 104                                                       
              0.038        0.024                                          
Compound of Ex. 105                                                       
              0.009        0.003                                          
Compound of Ex. 112                                                       
              0.009        0.003                                          
Compound of Ex. 114                                                       
              0.011        0.003                                          
Compound of Ex. 116                                                       
              0.012        0.0031                                         
Compound of Ex. 122                                                       
              0.015        0.003                                          
Compound of Ex. 123                                                       
              0.020        0.0032                                         
Compound of Ex. 126                                                       
              0.019        0.0053                                         
Compound of Ex. 127                                                       
              0.029        0.0059                                         
Compound of Ex. 128                                                       
              0.016        0.0046                                         
Compound of Ex. 129                                                       
              0.031        0.0048                                         
Compound of Ex. 139                                                       
              0.016        0.0041                                         
Compound of Ex. 140                                                       
              0.031        0.0056                                         
Compound of Ex. 143                                                       
              0.0066       0.0031                                         
Compound of Ex. 148                                                       
              0.027        0.017                                          
Compound of Ex. 173                                                       
              0.024        0.0053                                         
Compound of Ex. 175                                                       
              0.0084       0.0027                                         
Compound of Ex. 171                                                       
              0.0071       0.0031                                         
Compound of Ex. 169                                                       
              0.117        0.019                                          
Compound of Ex. 178                                                       
              0.029        0.0080                                         
Compound of Ex. 182                                                       
              0.028        0.010                                          
Compound of Ex. 187                                                       
              0.0078       0.0080                                         
Compound of Ex. 181                                                       
              0.015        0.0044                                         
Compound of Ex. 189                                                       
              0.034        0.012                                          
______________________________________
Experiment 3: Oxytocin receptor binding assay
According to the method of W. Y. Chan et al. [Endocrinology, 126, 2095-2101 (1990)], uterine muscle is taken out from a rat which has previously been injected subcutaneously with diethylstilbestrol the day before, and homogenized, which is used as a membrane preparation. The membrane preparation (0.2 mg), [3 H]-oxytocin (100000 dpm, 10-9 M), a test compound (10-9 -10-5 M) are incubated at 25° C. for one hour in 100 mM Tris-HCl buffer (pH 8.0, 250 μl) containing a 5 mM MgCl2, 1 mM MEDTA and 0.1% BSA. The mixture is filtered through the glass filter (GF/B) so as to separate the membrane preparation binding with [3 H]-oxytocin, and then, washed twice with the buffer (5 ml). This glass filter is put into a vial and mixed with Aquasole (liquid scintillation cocktail). The amount of [3 H]-oxytocin binding with the membrane is measured by liquid scintillation counter. The rate of the inhibitory effect of the test compound is estimated according to the following equation.
Inhibitory Rate (%)=100-[(C.sub.1 -B)/(C.sub.0 -B)]×100
C1 : The amount of [3 H]-oxytocin binding with the membrane in the presence of a test compound (known amount)
C0 : The amount of [3 H]-oxytocin binding with the membrane in the absence of a test compound
B: The amount of [3 H]-oxytocin binding with the membrane in the presence of the excess amount of oxytocin (5×10-6 M).
The results are expressed as IC50 value, which is the concentration of the test compound required to achieve the inhibitory rate in the rate of 50%.
The results are shown in the following Table 6.
              TABLE 6                                                     
______________________________________                                    
             IC.sub.50              IC.sub.50                             
Test compound No.                                                         
             (μM) Test Compound No.                                    
                                    (μM)                               
______________________________________                                    
Compound of Ex. 37                                                        
              1.14   Compound of Ex. 40                                   
                                     0.74                                 
Compound of Ex. 44                                                        
              0.307  Compound of Ex. 45                                   
                                     0.26                                 
Compound of Ex. 46                                                        
              0.36   Compound of Ex. 43                                   
                                     0.29                                 
Compound of Ex. 52                                                        
             1.6     Compound of Ex. 72                                   
                                     0.44                                 
Compound of Ex. 76                                                        
             1.5     Compound of Ex. 77                                   
                                    1.8                                   
Compound of Ex. 80                                                        
             1.0     Compound of Ex. 82                                   
                                    9.7                                   
Compound of Ex. 83                                                        
             6.6     Compound of Ex. 86*                                  
                                    17%                                   
Compound of Ex. 88                                                        
             4.5     Compound of Ex. 89                                   
                                    7.3                                   
Compound of Ex. 91*                                                       
             38%     Compound of Ex. 92*                                  
                                    38%                                   
Compound of Ex. 97                                                        
             1.8     Compound of Ex. 94                                   
                                     0.84                                 
Compound of Ex. 104                                                       
              0.51   Compound of Ex. 107                                  
                                     0.41                                 
Compound of Ex. 112                                                       
              0.28   Compound of Ex. 114                                  
                                     0.32                                 
Compound of Ex. 101                                                       
             3.5     Compound of Ex. 120                                  
                                     0.35                                 
Compound of Ex. 122                                                       
              0.64   Compound of Ex. 145                                  
                                    1.2                                   
Compound of Ex. 123                                                       
              0.32   Compound of Ex. 126                                  
                                     1.32                                 
Compound of Ex. 127                                                       
              0.68                                                        
______________________________________                                    
 *): Inhibitory Rate (%) at 10.sup.-5 M

Claims (29)

We claim:
1. A benzoheterocyclic compound of the formula (1): ##STR397## wherein R1 is hydrogen atom or a halogen atom, R2 is hydrogen atom, oxo group, a lower alkylidene group, hydroxy group, a lower alkoxy group, a lower alkenyloxy group, a hydroxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkylsulfonyloxy-substituted lower alkoxy group, a phthalimide-substituted lower alkoxy group, a hydroxy-substituted lower alkyl group, a group of the formula: --O--D--(CO)1 NR4 R5 (wherein D is a lower alkylene group, l is 0 or 1, R4 and R5 are the same or different and are hydrogen atom, a lower alkyl group, a lower alkanoyl group, a cycloalkyl group, or an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent, or R4 and R5 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group which may be intervened or not with a nitrogen atom, an oxygen atom or a sulfur atom, wherein said heterocyclic group may optionally be substituted by a lower alkyl group or a lower alkanoyl group), a group of the formula: -- E--(CO)1 NR6 R7 (wherein I is the same as defined above, E is a lower alkylene group, R6 and R7 are the same or different and are hydrogen atom, a lower alkyl group, an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent, or a lower alkanoyl group, or R6 and R7 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group which may be intervened or not with a nitrogen atom, an oxygen atom or a sulfur atom, wherein said heterocyclic group may optionally be substituted by a lower alkyl group, a lower alkanoyl group or a lower alkoxycarbonyl group), a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl-substituted lower alkyl group, an amino which may optionally be substituted by a lower alkyl group or a cycloalkyl group, a carboxy-substituted lower alkyl group, a lower alkylsulfonyloxy-substituted lower alkyl group, a phthalimide-substituted lower alkyl group, an imidazolyl-substituted lower alkyl group, a 1,2,4-triazolyl-substituted lower alkyl group, an amino-substituted lower alkanoyloxy group which may optionally have a lower alkyl substituent, or an imidazolyl-substituted lower alkoxy group,
R3 is hydrogen atom, a lower alkoxy group or a hydroxy-substituted lower alkyl group,
B1 and B2 are each methylene group
A is a 5- or 6-membered unsaturated heterocyclic residue having 1 to 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
R is a group of the formula: --NHRA or a group of the formula: ##STR398## wherein RA is a group of the formula: ##STR399## wherein m is an integer of 1 to 3, R18 is hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, nitro group, a lower alkoxycarbonyl group, carboxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a hydroxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkylsulfonyloxy-substituted lower alkoxy group, a phthalimide-substituted lower alkoxy group, or a group of the formula: --O--E--(CO)l NR19 R20 (wherein E and I are the same as defined above, R19 and R20 are the same or different and are hydrogen atom or a lower alkyl group, or R19 and R20 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group which may be intervened or not with a nitrogen atom or an oxygen atom, wherein said heterocyclic group may optionally be substituted by a lower alkyl group, or an amino group which may optionally be substituted by a lower alkanoyl group), thienylcarbonyl group, a cycloalkylcarbonyl group or a phenyl-lower alkanoyl group which may optionally have a lower alkyl substituent on the phenyl ring, or a salt thereof.
2. The benzoheterocyclic compound according to claim 1, wherein both B1 and B2 are methylene group, the unsaturated heterocyclic residue for A is imidazolyl, pyrrolyl, imidazolinyl, pyridyl, pyrimidinyl, oxazolyl, pyrazolyl, pyrazolinyl, thiazolyl, thiazolinyl, thienyl, furyl, pyranyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrrolinyl, or a salt thereof.
3. The benzoheterocyclic compound according to claim 1, wherein R is a group of the formula: ##STR400## and the unsaturated heterocyclic residue for A is imidazolyl, pyrrolyl, imidazolinyl, pyridyl, pyrimidinyl, oxazolyl, pyrazolyl, pyrazolinyl, thiazolyl, thiazolinyl, thienyl, furyl, pyranyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrrolinyl, or a salt thereof.
4. The benzoheterocyclic compound according to claim 1, wherein R3 is a lower alkoxy group or a hydroxy-substituted lower alkyl group, or a salt thereof.
5. The benzoheterocyclic compound according to claim 2, wherein A is pyridyl group, or a salt thereof.
6. The benzoheterocyclic compound according to claim 2, wherein A is thiazolyl group, or a salt thereof.
7. The benzoheterocyclic compound according to claim 2, wherein A is thienyl group or furyl group, and R is a group of the formula: --NHRA or a salt thereof.
8. The benzoheterocyclic compound according to claim 3, wherein A is pyridyl group, thiazolyl group, thienyl group or furyl group, and both B1 and B2 are methylene group, or a salt thereof.
9. The benzoheterocyclic compound according to claim 5, wherein R3 is hydrogen atom, R is a group of the of the formula: --NHRA R2 is hydrogen atom, oxo group, a lower alkylidene group, a lower alkoxy group, a lower alkenyloxy group, a hydroxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkylsulfonyloxy-substituted lower alkoxy group, a phthalimide-substituted lower alkoxy group, a group of the formula: --O--D--(CO)l NR4 R5 (wherein D is a lower alkylene group, l is 0 or 1, R4 and R5 are the same or different and are hydrogen atom, a lower alkyl group, a lower alkanoyl group, a cycloalkyl group, or an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent, or R4 and R5 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group which may be intervened or not with a nitrogen atom, an oxygen atom or a sulfur atom, wherein said heterocyclic group may optionally be substituted by a lower alkyl group or a lower alkanoyl group), a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl-substituted lower alkyl group, an amino which may optionally be substituted by a lower alkyl group or a cycloalkyl group, a lower alkylsulfonyloxy-substituted lower alkyl group, a phthalimide-substituted lower alkyl group, an imidazolyl-substituted lower alkyl group, a 1,2,4-triazolyl-substituted lower alkyl group, an amino-substituted lower alkanoyloxy group which may optionally have a lower alkyl substituent, or an imidazolyl-substituted lower alkoxy group, or a salt thereof.
10. The benzoheterocyclic compound according to claim 5, wherein R3 is hydrogen atom, R is a group of the formula: --NHRA defined in claim 1 ), R2 is a group of the formula: --E--(CO)l NR6 R7 (wherein E and I are the same as defined in claim 1, R6 and R7 are the same or different and are hydrogen atom, a lower alkyl group, an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent, or a lower alkanoyl group), or a salt thereof.
11. The benzoheterocyclic compound according to claim 5, wherein R3 is hydrogen atom, R is a group of the formula: --NHRA R2 is a group of the formula: --E--(CO)l NR6 R7 (wherein E and I are the same as defined above, R6 and R7 combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group which may be intervened or not with a nitrogen atom, an oxygen atom or a sulfur atom, wherein said heterocyclic group is pyrrolidinyl, piperidinyl, piperazinyl, morpholino or thiomorphlino, and said heterocyclic group may optionally be substituted by a lower alkyl group, a lower alkanoyl group or a lower alkoxycarbonyl group), or a salt thereof.
12. The benzoheterocyclic compound according to claim 5, wherein R3 is hydrogen atom, R is a group of the formula: --NHRA R2 is hydroxy group, a carboxy-substituted lower alkyl group or a hydroxy-substituted lower alkyl group, or a salt thereof.
13. The benzoheterocyclic compound according to claim 6, wherein R3 is hydrogen atom, R is a group of the formula: --NHRA R2 is hydrogen atom, oxo group, a lower alkylidene group, a lower alkoxy group, a lower alkenyloxy group, a hydroxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkylsulfonyloxy-substituted lower alkoxy group, a phthalimide-substituted lower alkoxy group, a group of the formula: --O--D--(CO)l NR4 R5 (wherein D is a lower alkylene group, l is 0 or 1, R4 and R5 are the same or different and are hydrogen atom, a lower alkyl group, a lower alkanoyl group, a cycloalkyl group, or an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent, or R4 and R5 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group which may be intervened or not with a nitrogen atom, an oxygen atom or a sulfur atom, wherein said heterocyclic group may optionally be substituted by a lower alkyl group or a lower alkanoyl group), a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl-substituted lower alkyl group, an amino which may optionally be substituted by a lower alkyl group or a cycloalkyl group, a lower alkylsulfonyloxy-substituted lower alkyl group, a phthalimide-substituted lower alkyl group, an imidazolyl-substituted lower alkyl group, a 1,2,4-triazolyl-substituted lower alkyl group, an amino-substituted lower alkanoyloxy group which may optionally have a lower alkyl substituent, or an imidazolyl-substituted lower alkoxy group, or a salt thereof.
14. The benzoheterocyclic compound according to claim 6, wherein R3 is hydrogen atom, R is a group of the formula: --NHRA R2 is a group of the formula: --E--(CO)1 NR6 R7 (wherein E and I are the same as defined in claim 1, R6 and R7 are the same or different and are hydrogen atom, a lower alkyl group, an amino-substituted lower alkyl group which may optionally have a lower alkyl substituent, or a lower alkanoyl group), or a salt thereof.
15. The benzoheterocyclic compound according to claim 6, wherein R3 is hydrogen atom, R is a group of the formula: --NHRA R2 is a group of the formula: --E--(CO)l NR6 R7 (wherein E and I are the same as defined above, R6 and R7 combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group which may be intervened or not with a nitrogen atom, an oxygen atom or a sulfur atom, wherein said heterocyclic group is pyrrolidinyl, piperidinyl, piperazinyl, morpholino or thiomorphlino, and said heterocyclic group may optionally be substituted by a lower alkyl group, a lower alkanoyl group or a lower alkoxycarbonyl group), or a salt thereof.
16. The benzoheterocyclic cyclic compound according to claim 6, wherein R3 is hydrogen atom, R is a group of the formula: --NHRA R2 is hydroxy group, a carboxy-substituted lower alkyl group or a hydroxy-substituted lower alkyl group, or a salt thereof.
17. The benzoheterocyclic compound according to any one of claims 9 to 16, wherein RA is a group of the formula: ##STR401## (in which R18 is a lower alkyl group or a halogen atom, and m is 1), or a salt thereof.
18. The benzoheterocyclic compound according to any one of claims 9 to 16, wherein RA is a group of the formula: ##STR402## (in which R18 is hydrogen atom, a lower alkoxy group, nitro group, a lower alkoxycarbonyl group, carboxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a hydroxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkylsulfonyloxy-substituted lower alkoxy group, a phthalimide-substituted lower alkoxy group, or a group of the formula: --O--E--(CO)l NR19 R20 (E and I are the same as defined above, R19 and R20 are the same or different and are hydrogen atom or a lower alkyl group, or R19 and R20 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group which may be intervened or not with a nitrogen atom or an oxygen atom, wherein said heterocyclic group may optionally be substituted by a lower alkyl group, or an amino group which may optionally be substituted by a lower alkanoyl group), and m is 1), or a salt thereof.
19. The benzoheterocyclic compound according to any one of claims 9 to 16, wherein RA is a group of the formula: ##STR403## (in which R18 is the same as defined in claim 1, and m is 2 or 3), or a salt thereof.
20. The benzoheterocyclic compound according to any one of claims 9 to 16 wherein RA is thienylcarbonyl group, a cycloalkylcarbonyl group or a phenyl-lower alkanoyl group which may optionally have a lower alkyl substituent on the phenyl ring, or a salt thereof.
21. The benzoheterocyclic compound according to claim 1, which is 7-chloro-5-[N-methyl-N-(2-diethylaminoethyl)amino]carbonylmethyl-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine.
22. The benzoheterocyclic compound according to claim 1, which is 7-chloro-5-carboxymethyl-1-[6-(2-bromobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine.
23. The benzoheterocyclic compound according to claim 1, which is 7-chloro-5-(2-hydroxyethyl)-1-[6-(2-methylbenzoylamino )nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine.
24. The benzoheterocyclic compound according to claim 1, which is 7-chloro-5-(2-acetylaminoethyl)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine.
25. The benzoheterocyclic compound according to claim 1, which is 7-chloro-5-hydroxy-1-[5-(2-methylbenzoylamino)-2-thiazolylcarbonyl]-2,3,4,5-tetrahydro-1H-benzazepine.
26. An vasopressin antagonist, which comprises as an active ingredient a benzoheterocyclic compound as set forth in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier or diluent.
27. An oxytocin antagonist, which comprises as an active ingredient a benzoheterocyclic compound as set forth in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier or diluent.
28. The benzoheterocyclic compound according to claim 5, wherein R3 is a hydrogen atom, R2 is a group of the formula:
--O--D(CO).sub.R NR.sup.4 S.sup.5
wherein R is a group of the formula:
--NHR.sup.A
wherein RA is a group of the formula: ##STR404## in which R18 is a lower alkyl group or a halogen atom, and m is 1, or a salt thereof.
29. The benzoheterocyclic compound according to claim 1, which is 7-chloro-5-(2-cyclopentylaminoethoxy)-1-[6-(2-chlorobenzoylamino)-nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine.
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